[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

US6180613B1 - AAV-mediated delivery of DNA to cells of the nervous system - Google Patents

AAV-mediated delivery of DNA to cells of the nervous system Download PDF

Info

Publication number
US6180613B1
US6180613B1 US08/467,044 US46704495A US6180613B1 US 6180613 B1 US6180613 B1 US 6180613B1 US 46704495 A US46704495 A US 46704495A US 6180613 B1 US6180613 B1 US 6180613B1
Authority
US
United States
Prior art keywords
vector
cells
aav
gene
expression
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US08/467,044
Other languages
English (en)
Inventor
Michael G. Kaplitt
Matthew J. During
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yale University
Rockefeller University
Original Assignee
Yale University
Rockefeller University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yale University, Rockefeller University filed Critical Yale University
Priority to US08/467,044 priority Critical patent/US6180613B1/en
Assigned to ROCKEFELLER UNIVERSITY, THE reassignment ROCKEFELLER UNIVERSITY, THE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KAPLITT, MICHAEL G.
Assigned to YALE UNIVERSITY reassignment YALE UNIVERSITY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DURING, MATTHEW J.
Priority to US09/548,176 priority patent/US6503888B1/en
Application granted granted Critical
Publication of US6180613B1 publication Critical patent/US6180613B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/48—Nerve growth factor [NGF]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/0004—Oxidoreductases (1.)
    • C12N9/0071—Oxidoreductases (1.) acting on paired donors with incorporation of molecular oxygen (1.14)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/0004—Oxidoreductases (1.)
    • C12N9/0071—Oxidoreductases (1.) acting on paired donors with incorporation of molecular oxygen (1.14)
    • C12N9/0073—Oxidoreductases (1.) acting on paired donors with incorporation of molecular oxygen (1.14) with NADH or NADPH as one donor, and incorporation of one atom of oxygen 1.14.13
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/88—Lyases (4.)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y114/00—Oxidoreductases acting on paired donors, with incorporation or reduction of molecular oxygen (1.14)
    • C12Y114/16—Oxidoreductases acting on paired donors, with incorporation or reduction of molecular oxygen (1.14) with reduced pteridine as one donor, and incorporation of one atom of oxygen (1.14.16)
    • C12Y114/16002—Tyrosine 3-monooxygenase (1.14.16.2)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y401/00—Carbon-carbon lyases (4.1)
    • C12Y401/01—Carboxy-lyases (4.1.1)
    • C12Y401/01028—Aromatic-L-amino-acid decarboxylase (4.1.1.28), i.e. tryptophane-decarboxylase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
    • C12N2750/00011—Details
    • C12N2750/14011—Parvoviridae
    • C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
    • C12N2750/14141—Use of virus, viral particle or viral elements as a vector
    • C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2840/00—Vectors comprising a special translation-regulating system
    • C12N2840/20—Vectors comprising a special translation-regulating system translation of more than one cistron
    • C12N2840/203—Vectors comprising a special translation-regulating system translation of more than one cistron having an IRES

Definitions

  • the present invention relates to the delivery of DNA to and the expression of delivered genes in, cells of the nervous system.
  • the first human gene therapy trial started in September 1990 and involved retrovirally-mediated transfer of the adenosine deaminase (ADA) gene into lymphocytes of patients with severe combined immunodeficiency (SCID).
  • SCID severe combined immunodeficiency
  • the favorable results of this trial stimulated further interest in gene therapy resulting in further 67 gene therapy clinical protocols approved by the NIH Recombinant DNA Advisory Committee (RAC) to date.
  • RAC NIH Recombinant DNA Advisory Committee
  • the first type of marking experiments used tumor infiltrating lymphocytes which were transduced in vitro with retroviral vectors prior to infusion into patients with cancer.
  • the second class of gene marking studies involved the attempt to detect residual tumor cells in marrow infused into patients following ablative chemotherapy.
  • HSV-1 neurotropic Herpes Simplex Virus
  • HSV vectors present several problems, including instability of expression and reversion to wild-type (see below).
  • a more recent development has been the use of adenoviral vectors.
  • Adenoviral vector studies have shown expression of marker genes into the rat brain persisting for two months although expression fell off dramatically (Davidson et al (1993) Nature Genetics 3:219-2223).
  • other investigators have used direct injection of a cationic liposome:plasmid complex obtaining low level and transient expression of a marker gene (Ono et al (1990) Neurosci. Lett. 117:259-263).
  • adenoviral vector has been used to induce low level transient expression of human al-antitrypsin (Bajoccchi et al (1993) 3:229-234).
  • the genome of the herpes simplex virus type-1 is about 150 kb of linear, double-stranded DNA, featuring about 70 genes. Many viral genes may be deleted without the virus losing its ability to propagate.
  • the “immediately early” (IE) genes are transcribed first. They encode trans-acting factors which regulate expression of other viral genes.
  • the “early” (E) gene products participate in replication of viral DNA.
  • the late genes encode the structural components of the virion as well as proteins which turns on transcription of the IE and E genes or disrupt host cell protein translation.
  • the viral DNA can enter a state of latency, existing as circular episomal elements in the nucleus. While in the latent state, its transcriptional activity is reduced. If the virus does not enter latency, or if it is reactivated, the virus produces numerous infectious particles, which leads rapidly to the death of the neuron. HSV-1 is efficiently transported between synaptically connected neurons, and hence can spread rapidly through the nervous system.
  • HSV vectors Two types have been utilized for gene transfer into the nervous system.
  • Recombinant HSV vectors involve the removal of an immediate-early gene within the HSV genome (ICP4, for example), and replacement with the gene of interest. Although removal of this gene prevents replication and spread of the virus within cells which do not complement for the missing HSV protein, all of the other genes within the HSV genome are retained. Replication and spread of such viruses in vivo is thereby limited, but expression of viral genes within infected cells continues.
  • Several of the viral expression products may be directly toxic to the recipient cell, and expression of viral genes within cells expressing MHC antigens can induce harmful immune reactions.
  • defective HSV vectors were employed as gene transfer vehicles within the nervous system.
  • the defective HSV vector is a plasmid-based system, whereby a plasmid vector (termed an amplicon) is generated which contains the gene of interest and two cis-acting HSV recognition signals. These are the origin of DNA replication and the cleavage packaging signal. These sequences encode no HSV gene products.
  • the amplicon is replicated and packaged into an HSV coat.
  • This vector therefore expresses no viral gene products within the recipient cell, and recombination with or reactivation of latent viruses by the vector is limited due to the minimal amount of HSV DNA sequence present within the defective HSV vector genome.
  • the major limitation of this system is the inability to eliminate residual helper virus from the defective vector stock.
  • the helper virus is often a mutant HSV which, like the recombinant vectors, can only replicate under permissive conditions in tissue culture.
  • the continued presence of mutant helper HSV within the defective vector stock presents problems which are similar to those enumerated above in regard to the recombinant HSV vector. This would therefore serve to limit the usefulness of the defective HSV vector for human applications.
  • HSV vectors of reduced toxicity and replication ability have been suggested, they can still mutate to a more dangerous form, or activate a latent virus, and, since the HSV does not integrate, achieving long-term expression would be difficult.
  • the adenovirus genome consists of about 36 kb of double-stranded DNA. Adenoviruses target airway epithelial cells, but are capable of infecting neural cells.
  • Recombinant adenovirus vectors have been used as gene transfer vehicles for non-dividing cells. These vectors are similar to recombinant HSV vectors, since the adenovirus E1a immediate-early gene is removed but most viral genes are retained. Since the E1a gene is small (roughly 1.5 kb) and the adenovirus genome is 1 ⁇ 3 the size of the HSV genome, other non-essential adenovirus are removed in order to insert a foreign gene within the adenovirus genome.
  • defective adenovirus vectors would be difficult to make as at least 20% of the Ad genome is required for packaging (about 27 kb) and vectors this size are difficult to work with.
  • the defective HSV vectors are small plasmids which replicate until the correct aggregate size is reached for proper packaging.
  • Adeno-Associated Virus is a defective parvovirus whose genome is encapsidated as a single-stranded DNA molecule. Strands of plus and minus polarity are both packaged, but in separate virus particles.
  • AAV can replicate under special circumstances in the absence of a helper virus, efficient replication requires coinfection with a helper virus of the herpesvirus or adenovirus family.
  • helper virus In the absence of the helper virus, AAV establishes a latent infection in which the viral genome exists as an integrated provirus in the host cell. (No AAV gene expression is required to establish a latent infection).
  • the integration of the virus is site-specific (chromosome 19).
  • AAV is a human virus
  • its host range for lytic growth is unusually broad.
  • Cell lines from virtually every mammalian species tested including a variety of human, simian, canine, bovine and rodent cell lines
  • helper virus e.g., canine adenovirus in canine cells.
  • no disease has been associated with AAV in either human or other animal populations, unlike both HSV and adenovirus.
  • AAV has been isolated as a nonpathogenic coinfecting agent from fecal, ocular and respiratory specimens during acute adenovirus infections, but not during other illnesses.
  • latent AAV infections have been identified in both human and nonhuman cells. Overall, virus integration appears to have no apparent effect on cell growth or morphology. See Samulski (1993) Curr. Op. Gen. Devel. 3:74-80.
  • AAV-2 The genome of AAV-2 is 4,675 bases in length and is flanked by inverted terminal repeat sequences of 145 bases each. These repeats are believed to act as origins for DNA replication.
  • the left frame encodes at least four non-structural proteins (the Rep group).
  • the Rep group There are two promoters P5 and P19, which control expression of these proteins.
  • the P5 promoter directs production of proteins Rep 78 and Rep 68, and the P19 promoter, Rep 52 and Rep 40.
  • the Rep proteins are believed to be involved in viral DNA replication, trans-activation of transcription from the viral promoters, and repression of heterologous enhancers and promoters.
  • Vp1 (91 kDa), Vp2 (72 kDa) and Vp3 (60 kDa).
  • Vp3 comprises 80% of the virion structure, while Vp1 and Vp2 are minor components.
  • McLaughlin et al ((1988) J. Virol. 62:1963-73) prepared two AAV vectors: dl 52-91, which retains the AAV rep genes, and dl 3-94, in which all of the AAV coding sequences have been deleted. It does, however, retain the two 145 base terminal repeats, and an additional 139 bases which contain the AAV polyadenylation signal. Restriction sites were introduced on either side of the signal.
  • Viral stocks were prepared by complementation with a recombinant AAV genome, which supplied the missing AAV gene products in trans but was itself too large to be packaged.
  • virus stocks were contaminated with wild type AAV (10% in the case of dl 3-94) presumably as a result of homologous recombination between the defective and the complementing virus.
  • Muro-Cacho et al ((1992) J. Immunother. 11:231-237) have used AAV-based vectors for gene transfer into both T- and B-lymphocytes.
  • Walsh et al ((1992) Proc. Nat. Acad. Sci . (USA) 89:7257-61) used an AAV vector to introduce a human gamma globulin gene into human erythroleukemia cells; the gene was expressed.
  • Flothe et al ((1993) J. Biol. Chem. 268:3781-90) delivered the cystic fibrosis transmembrane conductance regulator gene to airway epithelial cells by means of an AAV vector. See also Flotte et al (1992) Am. J. Respir. Cell. Mol. Biol. 7:349-56; Flotte et al (1993) Proc. Nat. Acad. Sci . ( USA ) 90:10613-17.
  • Adeno-associated virus has not been reported to naturally infect any nervous system cells, and AAV-derived vectors have not previously been used to transfect terminally differentiated, non-dividing cells. Nonetheless, the present invention demonstrates that an adeno-associated virus-derived vector may be used to deliver exogenous DNA to cells of the postnatal central and/or peripheral nervous system, including neurons and glia, even though these cells are non-dividing. Specificity may be achieved by anatomically specific delivery or by tissue specific expression.
  • the exogenous DNA preferably comprises a gene which encodes a gene product useful in the treatment of a nervous system disorder.
  • This gene in some embodiments, is operably linked to a promoter specific for particular cell types or regions within the nervous system. Because the AAV vector is integrated, stable, longterm expression (e.g., for greater than seven months) can be achieved.
  • FIG. 1 is a map of the AAV vector pAAVlac.
  • FIG. 2 is a schematic diagram outlining the relationship of the helper plasmid, AAV vector, adenovirus helper, etc.
  • FIG. 3 shows the effect of intrastriatal AAVth or AAVlac on apomorphine-induced rotational behavior in the rodent model of Parkinson's disease.
  • FIGS. 4A-F shows the immunohistochemical detection of hTH expression within the caudate nucleus of 6-OHDA lesioned rats following injection of AAVth.
  • A Absence of immunostaining in caudate following injection of AAVlac. No staining was ever observed in AAVlac animals, and staining was also always absent from the uninjected caudate from AAVth animals.
  • B,C TH expression in cells of the caudate nucleus 4 months following injection of AAVth. These sections were 30 ⁇ m in thickness, which prevented morphological identification of positive cells. Approximately 30 cells are seen at the site of injection (B) and cells are also seen 2 mm away from the injection site (C), although fewer cells are present at 2 mm.
  • D TH expression in caudate 1 week following AAVth injection. This section was 7 ⁇ m in thickness, revealing the neuronal appearance of the majority of positive cells. 50 positive cells can be seen in this section, which is representative of approximately 50 consecutively positive sections obtained from each short-term animal. Fewer cells were observed as far as 280 sections (2 mm) away from the injection site. This result was repeated twice at 1 week following injection, and comparable results were obtained from 9 animals at 48 hours and 9 animals at 24 hours post-injection.
  • E,F Double-label immunocytochemistry demonstrating neuronal TH expression.
  • E TH expression in a caudate cell (arrow) was revealed using a FITC-labelled secondary antibody.
  • F Neuronal identification of the TH-expressing cell (arrow) was obtained by sequentially staining the same section with an anti-neurofilament antibody and visualization with a Texas red-conjugated secondary antibody. Magnification: A-D, 400 ⁇ E,F, 630 ⁇ .
  • FIG. 5 shows plasmid pAAV-FlagTH-AADC.
  • This bicistronic construct contains the bicistronic construct with open reading frames for truncated tyrosine hydroxylase containing the N-terminal Flag epitope (Flag-TH) and aromatic amino acid decarboxylase (AADC).
  • Flag-TH N-terminal Flag epitope
  • AADC aromatic amino acid decarboxylase
  • TH converts tyrosine to L-Dopa
  • AADC converts L-Dopa to dopamine.
  • Between the two open reading frames is a sequence allowing ribosome re-entry and initiation of translation of a second open reading frame downstream from a translational stop codon. This is the internal ribosome entry site (IRES).
  • IRS internal ribosome entry site
  • RNA from the human cytomegalovirus immediate early gene promoter CMV promoter
  • CMV promoter human cytomegalovirus immediate early gene promoter
  • SV40 polyA SV40 virus
  • the entire insert is flanked by terminal repeats from the adeno-associated virus (AAV term.), which permits replication, excision and packaging of the insert in the presence of proteins provided by the helper plasmid pAAV/Ad and helper adenovirus.
  • the plasmid also contains standard plasmid sequences which permit replication and amplification of the DNA inside a bacterium (ori) and selection of bacterial colonies harboring the plasmid through resistance to ampicillin (amp).
  • ori adeno-associated virus
  • amp ampicillin
  • One of the several unique features of the AAV vector is that unlike other defective viral vectors, these plasmid sequences are lost when the DNA between the AAV termini is packaged.
  • FIG. 6 shows dopamine release into culture medium following plasmid transfection in 293T cells.
  • the first group of 4 samples represents 30 minutes following addition of tyrosine and tetrahydrobiopterin, while the second 4 samples were taken after 60 minutes.
  • Dopamine release was significant at 30 minutes, and even higher at 60 minutes, in cells transfected with pAAV-FlagTH-AADC and given tyrosine and tetrahydrobiopterin (TH/DC+).
  • TH/DC+ tyrosine and tetrahydrobiopterin
  • the vector of the present invention is a derivative of the adeno-associated virus, into which exogenous DNA has been introduced.
  • the vector be modified to reduce the possibility of rescue.
  • modifications can take the form of point mutations to one or more viral genes, which mutations either prevent expression of the gene altogether, or result in the expression of a modified gene product which is nonfunctional.
  • point mutations are reversible. Consequently, it is preferable that each undesired gene simply be deleted, which has the additional advantage of creating more room within the viral package for foreign DNA.
  • all of the viral genes be deleted, or otherwise inactivated, as in the known AAV vector dl3-94.
  • a vector retaining one or more AAV genes such as the known AAV vector dl52-91, may still be useful for gene delivery, although inferior to the preferred vectors.
  • susceptible cells are co-transfected with the AAV-derived vector and a suitable AAV-derived helper virus or plasmid.
  • the vector retains from AAV essentially only the recognition signals for replication and packaging.
  • the AAV vectors of the present invention may feature mutated inverted terminal repeats, etc., provided that the vector can still be replicated and packaged with the assistance of helper virus, and still establish a nonpathogenic latent infection in target cells.
  • the vector may further comprise one or more restriction sites into which foreign DNA may be cloned without interfering with packaging and replication. Preferably, at least one unique restriction site is provided.
  • the vector may also comprise one or more marker genes to facilitate genetic manipulation. Suitable marker genes include, but are not limited to, the neomycin and hygromycin resistance genes, bacterial lacZ, and the firefly luciferase gene.
  • the AAV-derived helper virus or plasmid may be any virus or plasmid which is capable, upon expression of the carried AAV genes, of providing proteins necessary for the replication and packaging of the vector in vitro in a suitable host cell, for the purpose of producing vector stock.
  • the helper virus or plasmid is one which has been engineered to reduce the risk of recombination between the helper DNA and the vector DNA.
  • the helper DNA may be an AAV in which the AAV inverted terminal repeats are replaced by the corresponding sequences of another virus, such as adenovirus (e.g., adenovirus type 5 DNA). See Samulski et al J. Virol. 63:3822-28.
  • helper adenovirus may be removed by heat inactivation at 56° C. for 30 minutes, or separated from packaged AAV vectors by centrifugation in a cesium chloride gradient.
  • the “exogenous DNA” of the present invention should be exogenous to both AAV and to the target cell.
  • the DNA may be synthetic DNA, complementary DNA, genomic DNA, or a combination thereof.
  • the DNA may be of any sequence or length, provided that it may be incorporated into the vector and delivered to target cells.
  • the exogenous DNA will have a length of about 10-5,000 bases.
  • the DNA is 100 to 4,000 bases.
  • the present invention may be used for gene therapy of any genetically-based or—acquired nervous system disorder.
  • An individual may be in need of gene therapy because, as a result of one or more mutations in the regulatory region and/or the coding sequence of one or more genes, a particular gene product is inappropriately expressed, e.g., has an incorrect amino acid sequence, or is expressed in the wrong tissues or at the wrong times, is underexpressed or overexpressed.
  • DNA delivered to that individual may be considered exogenous even though it is identical to a gene native to that individual's species, provided it differs in the regulatory or coding region from the cognate gene of the individual to whom it is delivered, and therefore encodes a different gene product or is expressed to a different degree and/or in different cells, under at least some conditions.
  • PD Parkinson's Disease
  • CP caudate-putamen
  • the mainstay of treatment is oral L-Dopa (and a peripheral decarboxylase inhibitor), which is converted to dopamine by endogenous AADC in the denervated CP.
  • Alternative pharmacological approaches include direct dopamine agonists including bromocriptine and apomorphine, as well as dopamine metabolizing enzyme (e.g. monoamine oxidase) inhibitors (MAOI), e.g. deprenyl.
  • MAOI monoamine oxidase inhibitors
  • a further implantation strategy includes a polymer or encapsulation device in which cells either dopamine-producing (e.g. PC 12) or genetically engineered cells (fibroblasts or neuronal cell lines which have been transduced, typically by retroviruses, to express tyrosine hydroxylase enzyme [THE]). These implants also disturb the neuronal circuitry, create significant injury in view of the size of the implant and moreover generate high local concentrations of dopamine to potentially toxic concentrations.
  • dopamine-producing e.g. PC 12
  • fibroblasts or neuronal cell lines which have been transduced, typically by retroviruses, to express tyrosine hydroxylase enzyme [THE]
  • the current invention has the significant advantages over the HSV-1 defective vector approach. Specifically, the reversion frequency of the defective HSV-1 virus is approximately 10 ⁇ 5 , and with the amounts of virus needed for in vivo studies sufficient wild type herpes infection occurs to result in toxicity and the death of experimental animals. Furthermore, although expression in the first two weeks is high, the level of vector gene expression beyond 2 weeks is reduced, perhaps to 5-20% of the initial expression.
  • the current invention also provides a major advantage over approaches which limit expression to THE.
  • PD and the denervated striatum in animal models of PD
  • the enzyme THE decreased by 80-100%, but the second enzyme in the dopamine biosynthetic pathway, AADC, is also decreased by approximately 85%.
  • AADC dopamine biosynthetic pathway
  • the vectors of the present invention are used to deliver the gene for tyrosine hydroxylase (Genbank HUMTHX, Accession No. M17589) to brain cells.
  • the gene for aromatic amino-acid decarboxylase (Genbank HUMDDC, Accession No. M76180) is similarly delivered, by the same or a separate vector.
  • transducing striatal cells in vivo to a dopaminergic phenotype is the first step in a gene therapy approach to PD.
  • PD becomes symptomatic when 80% of the dopamine neurons have been lost.
  • Degeneration is progressive and with further denervation patients become increasingly refractive to all current therapies and exhibit “On-Off” phenomenon with increasing freezing and complete immobility.
  • Transducing striatal cells with a viral vector to express dopamine synthesizing enzymes is purely a palliative approach and the underlying disease process will continue unabated. To this end vectors have been constructed expressing “neuroprotective or neurotrophic” factors to prevent further degeneration of dopaminergic neurons and promote regeneration.
  • GDNF glial-derived neurotrophic factor
  • Other neurotrophic factors of the NGF family have previously been expressed from HSV-1 vectors and shown to have neuroprotective effects (Federoff et al. These neurotrophic factors appear to act through tyrosine kinase receptors to prevent apoptosis or programmed cell death (PCD).
  • PCD programmed cell death
  • bcl-2 As the proto-oncogene bcl-2 can prevent neuronal PCD in vitro, an AAV vector has been constructed expressing bcl-2 to prevent PCD in vivo. This vector might therefore be considered for any neuronal degeneration in the brain including ischemia, epilepsy or brain trauma where secondary neuronal injury occurs via PCD.
  • gene therapy for PD could involve delivery, by AAV vectors, of the gene for GDNF (Genbank HUMGDNF02; Accession No. L19063), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) (EMBL HSNGF2; Accession No. X53655, and/or other members of the neurotrophin factor family including neurotrophin (NT)-3 (Genbank HUMBDNF; Accession No. M37762) and NT-4 (Genbank HUMPPNT4P; Accession No. M86528).
  • GDNF Genebank HUMGDNF02; Accession No. L19063
  • BDNF brain-derived neurotrophic factor
  • NGF2 nerve growth factor
  • EMBL HSNGF2 nerve growth factor
  • NT neurotrophin factor family including neurotrophin (NT)-3 (Genbank HUMBDNF; Accession No. M37762) and NT-4 (Genbank HUMPPNT4P; Accession No. M86528).
  • AAV vectors to deliver the genes for superoxide dismutase (SOD1 or SOD2) (GenBank HUMCUZNDI; Accession No. M12367; for SOD-1, EMBL HSSOD2G, Accession No. X65965 for SOD-2), catalase (EMBL HSCATR, Accession No. X04076), and/or glutathione peroxidase (MBL HSGSHPX, Accession No. Y00433).
  • TLE temporal lobe epilepsy
  • AED antiepileptic drugs
  • the current approach for these patients is to undergo a phased evaluation for consideration of resective surgery.
  • one temporal lobe is defined as the site of seizure origin (the epileptogenic region) and the medial temporal lobe including the anterior hippocampus is resected.
  • TLE is not a genetic disease and there is no established aetiology, however the disease results from an imbalance of excitation to inhibition with interventions enhancing excitation or blocking inhibition producing seizures and conversely the antagonism of excitation and enhancing of inhibition has an antiepileptic effect.
  • One gene therapy approach to TLE is to improve inhibition.
  • the adenosine A-1 receptor GenBank S56143; Accession S56143
  • cDNA has been inserted into the AAV vector.
  • adenosine has been shown to be the brain's natural anticonvulsant (acting through A-1 receptors) and levels of the receptor are decreased in the epileptogenic region, this strategy is likely to enhance inhibition and prevent seizures.
  • One related approach to increase inhibition is to increase expression of ion channels which alter neuronal excitability, specifically activity dependent channels including calcium-activated potassium channels and ATP-sensitive potassium channels.
  • a complementary approach is to express an antisense to excitatory receptors specifically glutamate receptors including NMDAR's, mGluR's and ionotropic glutamate receptors including both AMPA and kainate.
  • glutamate receptors including NMDAR's, mGluR's and ionotropic glutamate receptors including both AMPA and kainate.
  • expression of GluR6 using a HSV-1 vector induces epilepsy, it is reasonable to predict that a vector expressing antisense to these receptor types may inhibit seizures.
  • genes encoding adenosine A-1 receptor (GenBank S56143; Accession S56143, glutamate decarboxylase (GenBank S61898; Accession S61898), GABA-A receptor isoforms (EMBL HSGABAAA1; Accession X14766), calcium-dependent potassium channels (GenBank DROKCHAN, Accession M96840) and/or ATP-sensitive potassium channels (Ho, et al 1993 Nature 362:31-8) may be delivered by AAV vectors.
  • a mutant HSV has been used which can replicate only in dividing cells. This should result in destruction of dividing tumor cells while sparing non-dividing cells in the healthy brain.
  • results have been variable and not as impressive as would be desired. There have been no human trials of this method.
  • the second approach involves the insertion of the thymidine kinase (TK) gene from herpes simplex virus type 1 into a replication-deficient retroviral vector.
  • the retroviral vector only transferred the TK gene into dividing tumor cells, but could not transfer genes either into non-dividing tumor cells or healthy brain tissue.
  • TK phosphorylates ganciclovir, and the phosphorylated form disrupts DNA replication and thereby kills dividing cells. It was also found that nearby dividing cells which were not transduced with TK could also be killed. This was called the bystander effect, as it is believed that some phosphorylated drug can exit the transduced cell and enter nearby, non-transduced cells via gap junctions. Non-dividing cells are unaffected even by activated drug. This approach to tumor therapy is currently in clinical trials at the NIH.
  • the ability to phosphorylate drugs within non-dividing tumor cells and normal cells should create a greater pool of activated drug within the tumor.
  • non-dividing tumor cells containing the HSV TK gene should phosphorylate the drug and this could then enter a nearby dividing cell which may not have been transduced with the viral gene.
  • a non-dividing cell could permit destruction of a nearby, non-transduced cell, even though the transduced, non-dividing cell would not be adversely effected. In this manner, a greater population of dividing cells would be destroyed.
  • the second advantage is the ability of AAV vectors to integrate in non-dividing cells. If a retrovirus enters a non-dividing cell, reverse transcription does not occur and the vector is lost. When the AAV vector enters a non-dividing tumor cell, however, the vector should integrate into the host genome. Thus, if that tumor cell then re-enters cell division, the TK gene should be retained in that cell and all progeny. This should then render such previously quiescent tumor cells susceptible to destruction by ganciclovir or an analog. Since retroviral vectors are lost in non-dividing cells, and other DNA viral vectors do not reliably integrate within the host genome, the ability to retain the TK gene if a quiescent cell begins division is a property unique to the AAV vector.
  • the target cells of the vectors of the present invention are cells of the central or peripheral nervous systems of a mammal.
  • the cells are cells cultured in vitro.
  • the cells are part of a living mammal at the time the vector is delivered of the cell.
  • the mammal may be at any stage of development at the time of delivery, e.g., embryonic, fetal, infantile, juvenile or adult.
  • the vector may be delivered to cells of the central nervous system, cells of the peripheral nervous system, or both.
  • the vector When the vector is delivered to the cells of the central nervous system, it may be delivered to cells of the spinal cord, brainstem (medulla, pons, and midbrain), cerebellum, diencephalon (thalamus, hypothalamus), telencephalon (corpus striatum, cerebral cortex, or, within the cortex, the occipital, temporal, parietal or frontal lobes), or combinations thereof.
  • the peripheral nervous system it may be delivered to cells of the sensory and/or effector pathways.
  • the vector may be administered by stereotaxic microinjection, as exemplified in Example 2.
  • stereotaxic microinjection As exemplified in Example 2.
  • patients will have the stereotactic frame base fixed in place (screwed into the skull).
  • the brain with stereotactic frame base (MRI-compatible with fiducial markings) will be imaged using high resolution MRI.
  • the MRI images will then be transferred to a computer which runs stereotactic software.
  • a series of coronal, sagittal and axial images will be used to determine the target (site of AAV vector injection) and trajectory.
  • the software directly translates the trajectory into 3 dimensional coordinates appropriate for the stereotactic frame.
  • Burr holes are drilled above the entry site and the stereotactic apparatus positioned with the needle implanted at the given depth.
  • the AAV vector will then be injected at the target sites. Since the AAV vector will integrate into the target cells, rather than producing viral particles, the subsequent spread of the vector will be minor, and mainly a function of passive diffusion from the site of injection, prior to integration.
  • the degree of diffusion may be controlled by adjusting the ratio of vector to fluid carrier.
  • the vector may be injected into the cerebrospinal fluid, e.g., by lumbar puncture.
  • the vector may be injected into the spinal cord, or if more limited PNS distribution is sought, into the peripheral ganglia, or the flesh (subcutaneously or intramuscularly) of the body part of interest.
  • the vector will be administered via an intravascular approach.
  • the vector will be administered intra-arterially (carotid) in situations where the blood-brain barrier is disturbed. Such conditions include cerebral infarcts (strokes) as well as some brain tumors.
  • the vector will be administered during the “opening” of the blood-brain barrier achieved by infusion of hypertonic solutions including mannitol.
  • the user must be able to tolerate the delivery of the vector to cells other than those of the nervous system.
  • the vector may also be delivered intracerebroventricularly and/or intrathecally, for specific applications, including vectors expressing superoxide dismutase and neurotrophic factors for amyotrophic lateral sclerosis and Alzheimer's Disease and genes encoding enzymes of neurogenetic diseases e.g., Tay Sachs and Lesch-Nyan disease.
  • Additional routes of administration will be local application of the vector under direct visualization, e.g., superficial cortical application, or other non-stereotactic application.
  • the vector may be conjugated to a ligand (e.g., enkephalin) for which certain nervous system cells have receptors.
  • the conjugation may be covalent, e.g., a crosslinking agent such as glutaraldehyde, or noncovalent, e.g., the binding of an avidinated ligand to a biotinylated vector.
  • Another form of covalent conjugation is provided by engineering the helper virus used to prepare the vector stock so that one of the encoded coat proteins is a chimera of a native AAV coat protein and a peptide or protein ligand, such that the ligand is exposed on the surface.
  • the target cells may be human cells, or cells of other mammals, especially nonhuman primates and mammals of the orders Rodenta (mice, rats, rabbit, hamsters), Carnivora (cats, dogs), and Arteriodactyla (cows, pigs, sheep, goats, horses).
  • Rodenta mice, rats, rabbit, hamsters
  • Carnivora cats, dogs
  • Arteriodactyla cows, pigs, sheep, goats, horses.
  • the gene may be one which occurs in nature, a non-naturally occurring gene which nonetheless encodes a naturally occurring polypeptide, or a gene which encodes a recognizable mutant of such a polypeptide. It may also encode an mRNA which will be “antisense” to a DNA found or an mRNA normally transcribed in the host cell, but which antisense RNA is not itself translatable into a functional protein.
  • the precise nature of regulatory regions needed for gene expression may vary from organism to organism, but in general include a promoter which directs the initiation of RNA transcription. Such regions may include those 5′-non-coding sequences involved with initiation of transcription such as the TATA box.
  • the promoter may be constitutive or regulatable. Constitutive promoters are those which cause an operably linked gene to be expressed essentially at all times. Regulatable promoters are those which can be activated or deactivated. Regulatable promoters include inducible promoters, which are usually “off” but which may be induced to turn “on”, and “repressible” promoters, which are usually “on” but may be turned off. Many different regulators are known, including temperature, hormones, heavy metals, the product of the natively lined gene, and regulatory proteins. These distinctions are not absolute; a constitutive promoter may be regulatable to some degree.
  • the regulatability of a promoter may be associated with a particular genetic element, often called an “operator”, to which an inducer or repressor binds.
  • the operator may be modified to alter its regulation.
  • Hybrid promoters may be constructed in which the operator of one promoter is transferred into another.
  • the promoter may be an “ubiquitous” promoter active in essentially all cells of the host organism, e.g., the beta-actin or optomegalovirus promoters, or it may be a promoter whose expression is more or less specific to the target cells.
  • the tissue-specific promoters are essentially not active outside the nervous system, and the activity of the promoter optionally may be higher in some components of the nervous system than in others.
  • the promoter may be one which is active primarily in the central nervous system, or primarily in the peripheral nervous system, or it may be significantly active in both. If it is active in the CNS, it may be specific for the spinal cord, the brainstem (medulla, pons, midbrain, or combinations thereof), the cerebellum, the diencephalon (thalamus and/or hypothalamus), the telencephalon (the corpus striatum and/or the cerebral cortex, and, if the latter, the occipital, temporal, parietal and/or frontal lobes), or combinations thereof. The specificity may be absolute or relative.
  • the promoter may be specific for particular cell types, such as neurons or glial cells in the case of the CNS, or particular receptors or effectors in the case of the PNS. If it is active in glial cells, it may be specific for astrocytes, oligodendrocytes, ependymal cells, Schwann cells, or microglia. If it is active in neurons, it may be specific for particular types of neurons, e.g., motor neurons, sensory neurons, or interneurons.
  • cell types such as neurons or glial cells in the case of the CNS, or particular receptors or effectors in the case of the PNS. If it is active in glial cells, it may be specific for astrocytes, oligodendrocytes, ependymal cells, Schwann cells, or microglia. If it is active in neurons, it may be specific for particular types of neurons, e.g., motor neurons, sensory neurons, or interneurons.
  • tissue-specific promoter In general, to find a tissue-specific promoter, one identifies a protein which is expressed only (or primarily) in that tissue, and then isolates the gene encoding that protein. (The gene may be a normal cellular gene, or a viral gene of a virus which infects that cell). The promoter of that gene is likely to retain the desired tissue-specific activity when linked to another gene.
  • tissue specificity of a promoter may be associated with a particular genetic element, which may be modified, or transferred into a second promoter.
  • Both strong viral e.g.immediate early CMV, available on plasmid pCDNA1 from Invitrogen, Inc., San Diego, Calif.
  • relatively non-specific cellular promoters e.g., ⁇ -actin, Genbank HUMACTBET, K00790
  • strong viral e.g.immediate early CMV, available on plasmid pCDNA1 from Invitrogen, Inc., San Diego, Calif.
  • relatively non-specific cellular promoters e.g., ⁇ -actin, Genbank HUMACTBET, K00790
  • neuron specific promoters e.g., neuron specific enolase (EMBL HSENO2, X51956), AADC, neurofilament (Genbank HUMNFL, L04147), synapsin (Genbank HUMSYNIB, M55301), and serotonin receptor (Genbank S62283), promoters, as well as the combination of more broadly active promoters together with silencer elements which restrict expression to neurons.
  • neuron specific promoters e.g., neuron specific enolase (EMBL HSENO2, X51956), AADC, neurofilament (Genbank HUMNFL, L04147), synapsin (Genbank HUMSYNIB, M55301), and serotonin receptor (Genbank S62283), promoters, as well as the combination of more broadly active promoters together with silencer elements which restrict expression to neurons.
  • GFAP glial fibrillary acidic protein
  • S100 Genebank HUMS100AS, M65210
  • glutamine synthase EBL HSGLUS, X59834
  • Expression may be restricted to specific neuronal subpopulations using the following genetic elements:
  • Peptidergic promoters e.g., enkephalin (Genbank HUMENKPH1, K00488), prodynorphin, somatostatin (Genbank RATSOMG, J00787; Genbank HUMSOMI, J00306); monoaminergic promoters: tyrosine hydroxylase (Genbank M23597), dopamine ⁇ -hydroxylase (Genbank RATDBHDR, M96011), PNMT (EMBL HSPNMTB, X52730); for cholinergic neurons: choline acetyltransferase promoter (Genbank HUMCHAT1, M89915; EMBL HSCHAT, X56585).
  • the coding sequence must be operably linked to a promoter sequence functional in the target cell.
  • a promoter region would be operably linked to a coding sequence if the promoter were positioned so that, when the promoter was activated, the coding sequence was transcribed.
  • the coding sequences are operably linked if the linkage does not cause an error in the reading of the downstream sequence. In order to be “operably linked” it is not necessary that two sequences be immediately adjacent to one another.
  • the non-coding region 3′ to the gene sequence coding for the desired RNA product may be obtained.
  • This region may be retained for its transcriptional termination regulatory sequences, such as those which provide for termination and polyadenlylation.
  • the transcriptional termination signals may be provided. Where the transcriptional termination signals natively associated with the coding sequence are not satisfactorily functional in the expression host cell, then a different 3′ region, functional in the host cell, may be substituted.
  • an “expression vector” is a vector which (due to the presence of appropriate transcriptional and/or translational control sequences) is capable of expressing a DNA molecule which has been cloned into the vector and of thereby producing an RNA or protein product encoded by an expressible gene provided by said DNA. Expression of the cloned sequences occurs when the expression vector is introduced into an appropriate host cell. If a prokaryotic expression vector is employed, then the appropriate host cell would be any prokaryotic cell capable of expressing the cloned sequences. Similarly, when a eukaryotic expression vector is employed, e.g., for genetic manipulation prior to gene delivery, then the appropriate host cell would be any eukaryotic cell capable of expressing the cloned sequences.
  • the nucleic acid may comprise sequences homologous to genetic material of the target cell, whereby it may insert itself into the genome by homologous recombination, thereby displacing a coding or control sequence of a gene or deleting a gene altogether, provided that these sequences do not substantially interfere with integration of AAV.
  • the nucleic acid molecule is “antisense” to a genomic or other DNA sequence of the target organism (including viruses and other pathogens) or to a messenger RNA transcribed in cells of the organisms, which hybridizes sufficiently thereto to inhibit the transcription of the target genomic DNA or the translation of the target messenger RNA.
  • the efficiency of such hybridization is a function of the length and structure of the hybridizing sequences. The longer the sequence and the closer the complementarily to perfection, the stronger the interaction. As the number of base pair mismatches increases, the hybridization efficiency will fall off.
  • the GC content of the packaging sequence DNA or the antisense RNA will also affect the hybridization efficiency due to the additional hydrogen bond present in a GC base pair compared to an AT (or AU) base pair.
  • a target sequence richer in GC content is preferable as a target.
  • the gene encodes a ribozyme, i.e., an RNA with a desirable enzymatic activity.
  • Adeno-associated viral (AAV) vectors are non-pathogenic integrating DNA vectors in which all viral genes are removed (96% of the viral genome) and helper virus is completely eliminated.
  • An AAV vector expressing ⁇ -galactosidase was stereotactically injected into rat brain regions including striatum, hippocampus and substantia nigra. Vector DNA and transduced gene expression was detected from 1 day to 3 months post-injection.
  • a second vector expressing human tyrosine hydroxylase (TH) was generated.
  • This vector (AAVth) was injected into the denervated striatum of unilateral 6-hydroxydopamine-lesioned rats and TH immunoreactivity was obtained in striatal cells, including both glia and neurons, to 4 months. There was no evidence of pathology or toxicity in any animal treated with AAV vectors. Initial data indicates that TH transduction in the striatum via an AAV vector yields significant behavioral recovery in lesioned rats compared with AAVlac controls.
  • Plasmids Plasmid pSub201 (Samulski et al (1989) J. Virol. 63:3822-28) was digested with XbaI to remove nearly the entire AAV genome, leaving only the terminal repeats.
  • a CMV promoter-lacZ gene-SV40 polyA signal cassette was isolated from plasmid pHCL (Kaplitt et al (1991) Mol. Cell. Neurosci. 2:320-30) by digestion with SpeI and XbaI, and this was inserted into XbaI-digested pSub201 to create pAAVlac.
  • a second plasmid was created (pAAV-CMV-polyA) by digestion of pAAVlac with HindIII and XbaI to remove the lacZ gene and polyA signal, followed by insertion of a HindIII-XbaI fragment from pREP4 (Invitrogen), containing a polylinker and SV40 polyA signal.
  • This plasmid was then digested with HindIII and BamHI, followed by insertion of a human tyrosine hydroxylase (hTH) cDNA (O'Malley et al (1987) Biochemistry 26:6910-14) in order to create pAAVth.
  • hTH human tyrosine hydroxylase
  • plasmids (pAAVlac or pAAVth) were transfected via the calcium phosphate method (Graham et al (1973) Virology 52:496-67) into 293T cells, a variant of 293 cells (Graham et al (1977) J. Gen. Virol. 36:59-74), (obtained from D. Baltimore) which constitutively express both the adenovirus E1a protein and the SV40 T antigen.
  • the vector plasmids were co-transfected along with the helper plasmid pAd8, which provides necessary replication and structural proteins.
  • adenovirus strain dl309 Jones and Shenk (1978) Cell 13:181-88) (obtained from Thomas Shenk, Princeton University). Following full cytopathic effect, virus was harvested by multiple freeze/thaw cycles. Viral stocks were then heated to 56° C. for 30 minutes in order to inactivate residual adenovirus (Samulski et al 1989). Vector titers were obtained by histochemical assay for X-gal (Kaplitt et al (1991) Mol. Cell. Neurosci.
  • Immunocytochemistry and X-Gal Histochemistry For analysis of brain sections from animals injected with AAVlac, tissues were fixed by intracardiac perfusion with 2% paraformaldehyde/5 mM EGTA/2 mM MgCl 2 in 0.1 M HEPES (pH 7.3). The addition of EGTA eliminates any background staining due to endogenous cellular enzymes. Tissue culture cells were fixed with 2% formaldehyde/0.2% glutaraldehyde in PBS (pH 7.2). X-gal histochemistry for detection of ⁇ -galactosidase expression was performed as described previously.
  • Slides were coverslipped and coverslips were anchored on one side with nail polish. Slides were placed on aluminum foil on the block of a thermal cycler, and the temperature was raised to 82° C. Coverslips were raised, 2 ⁇ l of enzyme mix (1 ⁇ PCR buffer/2U/ml Taq) was added to each slide and coverslips were dropped. Slides were covered in mineral oil, and the following profile was run: 35 cycles of 2 minutes, 55° C.; 2 minutes, 72° C.; 2 minutes, 94° C. Slides were placed in xylene to remove the mineral oil, and sections were re-hydrated. PCR product was detected in situ with an alkaline phosphatase-labelled anti-digoxigenin antibody, according to the manufacturer's instructions.
  • mice and Tissue Preparation Male Sprague-Dawley rats were used in all studies. Animals were treated according to the NIH Guidelines for Animal Care and Use. For surgical procedures, animals were anesthetized with a mixture of enflurane and NO 2 . Stereotaxic microinjection was used for all brain region injections, and coordinates were determined according to the atlas of Paxinos and Watson, The Rat Brain in Stereotaxic Coordinates , (Academic Press, Sydney, Australia: 1982). Tissue for immunocytochemistry was removed and quickly frozen mounting medium. 5 ⁇ m sections were taken with a cryostat, and sections were fixed in buffered formalin. Tissue for X-gal histochemistry was prepared as described above.
  • Unilateral Substantia Nigra Lesioning Unilateral nigral lesions were generated using the method of Perese et al (1989) Brain Res. 494:285-93, as previously described, During et al (1992) Exp. Neurol. 115:193-99.
  • male Sprague Dawley rats 290-310 grams were anesthetized with xylazine/ketamine and placed in a Kopf stereotactic frame. The skull was exposed and burr holes drilled above the left substantia nigra, Lambda +3.5, L 2.15.
  • Rats were tested 10-16 days following the 6-OHDA injections. They were placed in a hemispherical rotameter and the total number of complete body turns was recorded from 15-20 minutes following the administration of apomorphine (1 mg/kg) as described by Hefti et al. (1980), Brain Res., 195:123-27. A minimum of three tests separated by at least 2 weeks was used to generate a basal rotation rate. Animals which consistently exhibited stable (less than 25% variation) asymmetrical rotational behavior of greater than 10 turns per minute were randomly selected for either AAVlac or AAVth injection.
  • Rats meeting the above behavioral criteria of a near complete lesion were anesthetized with ketamine/xylazine (70 mg/7 mg per kg) and placed in a kopf stereotactic frame. The skull was exposed and holes drilled above the denervated striatum (left) at Paxinos & Watson coordinates of AP 0.2, L 2.6 and AP 1.5, L 2.0 and L 3.0. Either AAVlac of AAVth was injected slowly using a Hamilton syringe into each of three sites at a DV depth of 5 mm. Each injection volume was 2 ⁇ l. Rats were tested for apomorphine-induced rotational behavior at one and two months following surgery.
  • IHC immunohistochemical
  • Sections were initially incubated in blocking buffer (5% Goat Serum (GS)/5% Normal Horse Serum (NHS) in 1 M Phosphate Buffer Saline (PBS). Sections were than incubated in primary antibodies diluted in blocking buffer (mouse anti-TH [Boehringer Mannheim, 1:200], mouse anti-NF [Sigma, 1:400], rabbit anti-TH [Chemicon International, 1:3000]rabbit anti-GFAP [gift from Dept.
  • blocking buffer 5% Goat Serum (GS)/5% Normal Horse Serum (NHS) in 1 M Phosphate Buffer Saline (PBS).
  • Primary antibodies diluted in blocking buffer (mouse anti-TH [Boehringer Mannheim, 1:200], mouse anti-NF [Sigma, 1:400], rabbit anti-TH [Chemicon International, 1:3000]rabbit anti-GFAP [gift from Dept.
  • AAV Adeno-associated Virus
  • the bacterial lacZ gene was inserted into plasmid psub20l (Samulski et al (1989) J. Virol. 63:3822-28) between the termini of the AAV genome. These termini contain the recognition signals for cleavage and packaging into an AAV vector.
  • the lacZ gene encodes the bacterial enzyme ⁇ -galactosidase; which produces an insoluble blue precipitate upon reaction with the appropriate substrate.
  • the human cytomegalovirus (CMV) immediate-early promoter was used to direct gene expression, and an SV40 polyadenylation signal was placed downstream of the lacZ gene (FIG. 1 ).
  • AAV vectors were then titered by infection of cultured 293 cells, histochemical staining for ⁇ -galactosidase expression and counting of blue cells. There was no difference in the number of cells observed at 1 and 5 days following infection, demonstrating an absence of vector replication and spread.
  • nb positive cells were observed following infection with the resulting stock. This indicates that the lacZ gene was packaged into an AAV virus which was incapable of autonomous replication while residual adenovirus was completely eliminated.
  • AAV Vectors Can Transfer and Stably Express A Foreign Gene in The Adult Rat Brain
  • AAVlac was stereotaxically microinjected into various regions of the adult rat brain, including caudate nucleus, amygdala, striatum and hippocampus. Animals were initially sacrificed between 1 and 3 days following injection and sections were processed for X-gal histochemistry. Positive cells were demonstrated within each region. The efficiency of gene transfer into the brain appeared to be at least equivalent to that observed previously with HSV or adenovirus vectors.
  • PCR polymerase chain reaction
  • the AAV Vector Yields Expression of Tyrosine Hydroxylase in the Caudate Nucleus of 6-OHDA Lesioned Rats
  • Parkinson's Disease is a neurodegenerative disorder characterized by loss of the nigrostriatal pathway and is responsive to treatments which facilitate dopaminergic transmission in the caudate-putamen.
  • PD Parkinson's Disease
  • PNAS USA
  • HSV-1 vector expressing TH has shown that this approach may be a viable alternative to tissue transplantation.
  • Soc. Neurosci Abstr. 18:331-8 Soc. Neurosci Abstr. 18:331-8.
  • HSV-1 vectors currently have several limitations as described above. In order to generate a vector which may have therapeutic utility in human PD patients, we inserted a human TH cDNA (form II) (O'Malley et al. Biochemistry 26:6910-14) into our AAV vector (AAVth). AAVth was packaged and helper virus was eliminated as described above for AAVlac.
  • Unilateral 6-hydroxydopamine lesions of the substantia nigra have been used to generate an established rodent model of PD.
  • the asymmetry caused by differing postsynaptic receptor sensitivities between the denervated and intact striatum results in rotational behavior following systemic administration of dopaminergic agents, such as apomorphine (Hefti et al. (1980) Brain Res. 195:123-7).
  • dopaminergic agents such as apomorphine
  • the rate of asymmetrical rotation is directly related to the severity of the striatal dopamine deficit and this model has predictive ability in defining treatments which have therapeutic efficacy in PD.
  • Lesioned rats were tested for apomorphine-induced rotation every two weeks oil a minimum of three occasions, and animals that satisfied behavioral criteria of >95% lesion efficacy (>10 rotations/minutes) were identified (Hefti et al. 1980).
  • AAVth or AAVlac virus, or vehicle alone (phosphate buffered saline, [PBS]), was delivered by stereotactic injection into the denervated striatum. Animals were tested for apomorphine-induced asymmetrical rotation at 2, 4 and 9 weeks. The rotational behavior of the AAVlac injected animals was similar to the PBS injected animals. In contrast, AAVth injected animals demonstrated significant behavioral recovery (FIG. 3 ), compared to AAVlac or PBS injected groups (control groups). The average behavioral recovery caused by AAVth was 31 ⁇ 6% at 4 weeks and was maintained at 32 ⁇ 3% at 9 weeks (P ⁇ 0.01) after injection.
  • TH TH immunoreactivity within the striatum is limited to the dopaminergic afferent fibers in unlesioned animals and is absent in the completely denervated striatum.
  • TH-IR striatal TH immunoreactivity
  • TH monoclonal antibody a rabbit polyclonal antibody to glial fibrillary acidic protein (GFAP), a marker of astrocytes and oligodendrocytes.
  • Other sections were double labelled with TH antibody and antibodies for glutamic acid decarboxylase (GAD), a marker of GABAergic neurons, the predominant neuronal population of the neostriatum. Double labelling revealed that the majority of TH-IR cells were immunoreactive for GAD, while a small percentage of TH-IR cells were GFAP positive.
  • GAD glutamic acid decarboxylase
  • GABAergic neurons constitute approximately 95% of the intrinsic striatal neuron population with choline acetyl transferase (ChAT, cholinergic) positive cells making up the remainder. Double labelling with TH and ChAT also revealed expression of vector encoded TH in striatal cholinergic neurons.
  • the titre of the AAVth stock used for these in vivo studies was 5 ⁇ 10 6 infectious particles (i.p.)/ml. Therefore a single injection of 2 ⁇ l would result in 10,000 positive cells if the efficiency of infection was 100% and each i.p. infected a different cell.
  • a single injection of 2 ⁇ l would result in 10,000 positive cells if the efficiency of infection was 100% and each i.p. infected a different cell.
  • previous infection of AAV does not prevent subsequent re-infection or multiple particles infecting the same cell, in the immediate vicinity of the injection we might expect cells to have multiple infection.
  • AAVth might also infect axons and terminals and following retrograde transport be expressed in the cell body regions of the striatal afferents (e.g., the surviving dopamine nigral neurons, the cortex, reticular nucleus of the thalamus and dorsal raphe nuclei).
  • the total number of striatal cells containing TH-IR consistently exceeded 1000 for each of the 2 ⁇ l injections suggesting a minimum of 10% in vivo efficiency, significantly greater than previous observations using defective HSV-1 vectors (@ 2%).
  • the level of expression was also examined at times ranging from 3 days to 7 months. Expression persisted throughout this 7 month period, although the level of expression diminished by approximately 50%.
  • Dopamine synthesis is catalyzed by two enzymes, TH and aromatic acid decarboxylase (AADC).
  • TH aromatic acid decarboxylase
  • AADC aromatic acid decarboxylase
  • the reaction catalyzed by TH results in the synthesis of L-Dopa, and this is the rate-limiting step in the synthesis of dopamine.
  • Dopamine then results from conversion of L-Dopa by AADC.
  • striatum does not contain cells which endogenously produce TH, there are a small percentage of striatal cells which produce AADC. Therefore, behavioral recovery in animals treated with AAVth (or other approaches using TH alone) presumably occurs secondary to conversion of the resulting L-Dopa to dopamine by endogenous striatal AADC.
  • TH gene was truncated, eliminating the 5′ end. Truncation of the TH gene has actually been shown to increase enzymatic activity due to removal of an amino terminal regulatory domain. (Walker et al (1994) Bioch. Biophys. Acta 1206:113-119). Therefore, this served a functional purpose as well as increasing the space available for other genetic elements.
  • a small synthetic oligonucleotide, encoding a novel epitope was attached to the 5′ end of the truncated TH. This novel epitope, termed “Flag”, is recognized by a commercially available monoclonal antibody; this provides an independent and unambiguous marker for expression of AAV-transduced T14 in vivo.
  • the AADC gene was inserted into the vector. Creation of two independent expression units, with two promoters and two polyadenylation signals, would have resulted in an insert size so large as to be incompatible with the constraints of the AAV vector. Therefore, an IRES element was inserted between the Flag-TH and AADC cDNAs. Most eukaryotic mRNAs are monocistronic; they contain a single-open reading frame, and when translation of a peptide is stopped and the ribosome falls off of the transcript, additional downstream translational start sites cannot be utilized.
  • IRES Internal Ribosome Entry Site
  • CMV CMV
  • SV40 mRNA polyadenylation signal
  • each of the independent expression parameters were tested in culture.
  • the plasmid was transfected into 293T cells, and then the following day the substrate tyrosine and an essential co-factor (tetrahydrobiopterin) were added to the tissue culture medium of some of these cultures.
  • additional cells were transfected with the plasmid AAVlac or were mock-transfected. Samples of medium were obtained at 30 minutes and 60 minutes after addition of co-factors (or mock treatment), and these were analyzed for the presence of dopamine by high-performance liquid chromatography (HPLC). As indicated in FIG.
  • AAVFlag-TH contains a monocistronic insert with the Flag-TH open reading frame but lacking both the IRES sequence and the AADC open reading frame. 293T cells were then transfected with AAV Flag-TH/AADC, AAVFlag-TH, AAVlac or no plasmid.
  • the great potential of the bicistronic vector as a therapeutic agent for Parkinson's disease has led to the rapid initiation of primate studies.
  • the primate model of Parkinson's disease is considered to be the gold-standard model for evaluation of potential therapies prior to entering human clinical trials.
  • This model was originally developed from the observation in the early 1980s that groups of younger people were developing a neurodegenerative disorder strikingly similar to idiopathic Parkinson's disease. The source of this disorder was traced to the use of a street drug, and the specific causative agent was found to be 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Langston (1985) Trends Pharmacol. Sci. 6:375-378).
  • MPTP 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine
  • MPTP monoamine oxidase B
  • MAO-B monoamine oxidase B
  • This compound is then selectively concentrated within the dopaminergic neurons of the substantia nigra via an energy-dependent, presynaptic uptake mechanism. This may be enhanced by the ability of neuromelanin, found within nigral neurons, to bind MPP+ (D'Amato et al (1986) Science 231:987-989).
  • MPP+ is a potent neurotoxin which eventually causes the degeneration of nigral dopaminergic neurons and loss of the nigro-striatal dopamine pathway, as is seen in Parkinson's disease.
  • Biochemical analysis of tissue samples from treated primates further indicated that the vector did cause an increase in striatal dopamine (During et al (1994)).
  • the level of dopamine from a striatal tissue sample near the site of AAV injection was 18.93 ng/mg protein.
  • An equivalent tissue sample from the uninjected, contralateral striatum yielded a dopamine level of 7.97 ng/mg protein.
  • Tissue samples from distal sites on the injected and uninjected sides resulted in dopamine levels of 2.48 ng/mg and 2.27 ng/mg respectively.
  • peripherally administered MPTP should result in roughly equal lesions to the substantia nigra bilaterally, the approximately 140% increase in dopamine levels in the injected striatum compared with the untreated side suggests that the AAV vector resulted in expression of functionally active enzymes.
  • a second study employed more severely lesioned primates in order to determine whether there is a therapeutic potential for AAV Flag-TH/AADC. Subjects were divided into two groups, with the treated group receiving AAV Flag-TH/AADC and controls receiving AAVlac. All animals received bilateral stereotaxic injections, with the same virus infused into the striatum on both sides of the brain. Subjects were then followed for 2.5 months after surgery. Observations suggest that the bicistronic vector resulted in sustained improvement in parkinsonian behavior (During et al (1994). Monthly assessments of control and treated animals by blinded caretakers reported virtually no change in the behavior of animals which were subsequently determined to have been controls, while the response in treated subjects varied from modest improvement to substantial recovery of function.
  • AAV vectors may result in behavioral recovery of parkinsonian primates. It should also be noted that in both primate studies, there was no behavioral or histological evidence of toxicity due to the AAV vector. All of the data indicate that safe, long-term improvement of human neurological diseases may be possible via genetic modification of adult brain cells in vivo using AAV vectors.
  • AAV vector An additional AAV vector has been developed as an alternative approach to the treatment of Parkinson's disease.
  • the majority of therapeutic strategies for PD have concentrated upon increasing striatal dopamine levels.
  • behavioral recovery in animal models has been repeatedly demonstrated, this is not a cure for the disease but rather symptomatic palliation.
  • Neuronal degeneration in the substantia nigra is the pathological result of the disease process, and progression of neurodegeneration is not altered by increasing striatal dopamine.
  • growth factors such as glial-derived neurotrophic factor (GDNF) can be protective of and trophic for neurons of the substantia nigra (Lin et al (1993) Science 260:1130-1132). Therefore, an AAV vector was created containing the cDNA for GDNF under the control of the CMV promoter.
  • GDNF glial-derived neurotrophic factor
  • Rats were lesioned with 6-OHDA and subsequently received injections AAVgdnf, AAVlac or saline into the lesioned substantia nigra (During et al (1994)). After several weeks, dopamine release into the striatum on the lesioned side was determined using intracerebral microdialysis. This technique permits sampling of local neurotransmitter release within a specific brain region of living animals (During and Spencer (1993) Lancet 341:1607-1610). Baseline dopamine levels were sampled three times and there was no difference between groups. Animals were then treated with potassium which induces release of dopamine from presynaptic terminals.
  • gene therapy can be useful for both palliation of PD through striatal expression of synthetic enzymes for dopamine as well as for treatment of the underlying disease process by expressing growth factors which may protect or regenerate dopaminergic neurons.
  • the present invention is the first demonstration that AAV vectors can safely and efficiently transfer and express a foreign gene marker gene (lacZ) in the adult rat brain. Furthermore, stability of viral DNA and lacZ expression within the brain was observed for at least 7 months with no evidence of pathology or toxicity. Expression of human tyrosine hydroxylase (hTH) was demonstrated in both neurons and glia of rat brains which had previously received unilateral 6-hydroxydopamine (6-OHDA) lesions in the substantia nigra.
  • 6-OHDA 6-hydroxydopamine

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Genetics & Genomics (AREA)
  • General Health & Medical Sciences (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Molecular Biology (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biotechnology (AREA)
  • Veterinary Medicine (AREA)
  • Microbiology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biophysics (AREA)
  • Toxicology (AREA)
  • Plant Pathology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Physics & Mathematics (AREA)
  • Virology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Diabetes (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Endocrinology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
US08/467,044 1994-04-13 1995-06-06 AAV-mediated delivery of DNA to cells of the nervous system Expired - Lifetime US6180613B1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US08/467,044 US6180613B1 (en) 1994-04-13 1995-06-06 AAV-mediated delivery of DNA to cells of the nervous system
US09/548,176 US6503888B1 (en) 1994-04-13 2000-04-13 AAV-mediated delivery of DNA to cells of the nervous system

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US22731994A 1994-04-13 1994-04-13
US08/467,044 US6180613B1 (en) 1994-04-13 1995-06-06 AAV-mediated delivery of DNA to cells of the nervous system

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US22731994A Continuation-In-Part 1994-04-13 1994-04-13

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US09/548,176 Continuation US6503888B1 (en) 1994-04-13 2000-04-13 AAV-mediated delivery of DNA to cells of the nervous system

Publications (1)

Publication Number Publication Date
US6180613B1 true US6180613B1 (en) 2001-01-30

Family

ID=22852632

Family Applications (2)

Application Number Title Priority Date Filing Date
US08/467,044 Expired - Lifetime US6180613B1 (en) 1994-04-13 1995-06-06 AAV-mediated delivery of DNA to cells of the nervous system
US09/548,176 Expired - Lifetime US6503888B1 (en) 1994-04-13 2000-04-13 AAV-mediated delivery of DNA to cells of the nervous system

Family Applications After (1)

Application Number Title Priority Date Filing Date
US09/548,176 Expired - Lifetime US6503888B1 (en) 1994-04-13 2000-04-13 AAV-mediated delivery of DNA to cells of the nervous system

Country Status (7)

Country Link
US (2) US6180613B1 (fr)
EP (1) EP0755454B1 (fr)
JP (3) JPH10501686A (fr)
AT (1) ATE386131T1 (fr)
CA (1) CA2187626C (fr)
DE (1) DE69535703T2 (fr)
WO (1) WO1995028493A1 (fr)

Cited By (275)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020091094A1 (en) * 2000-05-23 2002-07-11 During Matthew J. Glutamic acid decarboxylase (GAD) based delivery system
US6436708B1 (en) * 1997-04-17 2002-08-20 Paola Leone Delivery system for gene therapy to the brain
US20020172664A1 (en) * 2001-03-14 2002-11-21 Keiya Ozawa Methods of treating Parkinson's disease using recombinant adeno-associated virus virions
US6503888B1 (en) * 1994-04-13 2003-01-07 The Rockefeller University AAV-mediated delivery of DNA to cells of the nervous system
US20030036511A1 (en) * 1996-12-13 2003-02-20 Chiron Corporation Analysis and separation of platelet-derived growth factor proteins
WO2003015713A2 (fr) * 2001-08-20 2003-02-27 Maiken Nedergaard Traitement de tumeurs gliales avec des antagonistes du glutamate
US20030061184A1 (en) * 2001-09-27 2003-03-27 Csem Centre Suisse D'electronique Et De Microtechnique S.A. Method and a system for calculating the values of the neurons of a neural network
US20030065155A1 (en) * 2000-03-06 2003-04-03 Nassim Usman Nucleic acid sensor molecules
US20030082145A1 (en) * 1994-06-06 2003-05-01 Johnson Philip R. Adeno-associated virus materials and methods
US20030105051A1 (en) * 2001-05-29 2003-06-05 Mcswiggen James Nucleic acid treatment of diseases or conditions related to levels of HER2
WO2003053476A1 (fr) * 2001-12-19 2003-07-03 Lijun Wang Administration de gdnf induite par le virus adeno-associe dans des muscles du squelette
US20030140362A1 (en) * 2001-06-08 2003-07-24 Dennis Macejak In vivo models for screening inhibitors of hepatitis B virus
US20030190635A1 (en) * 2002-02-20 2003-10-09 Mcswiggen James A. RNA interference mediated treatment of Alzheimer's disease using short interfering RNA
US20030191077A1 (en) * 2001-04-05 2003-10-09 Kathy Fosnaugh Method and reagent for the treatment of asthma and allergic conditions
US20030203870A1 (en) * 2000-02-11 2003-10-30 Ribozyme Pharmaceuticals, Inc. Method and reagent for the inhibition of NOGO and NOGO receptor genes
US20030223971A1 (en) * 1996-03-06 2003-12-04 Kurtzman Gary J. Gene therapy for the treatment of solid tumors using recombinant adeno-associated virus vectors
US20030228284A1 (en) * 2002-04-30 2003-12-11 University Of North Carolina At Chapel Hill Secretion signal vectors
US20040009510A1 (en) * 2000-03-06 2004-01-15 Scott Seiwert Allosteric nucleic acid sensor molecules
US20040016013A1 (en) * 2002-07-18 2004-01-22 Gonzalo Hortelano Transgenic animals produced using oral administration of a genetic agent coupled to a transporting agent
US20040014698A1 (en) * 2002-07-18 2004-01-22 Gonzalo Hortelano Oral administration of therapeutic agent coupled to transporting agent
US20040018520A1 (en) * 2002-04-22 2004-01-29 James Thompson Trans-splicing enzymatic nucleic acid mediated biopharmaceutical and protein
US20040086490A1 (en) * 1996-09-11 2004-05-06 Sumesh Kaushal AAV4 vector and uses thereof
US20040110266A1 (en) * 2002-05-17 2004-06-10 Chiorini John A. Scalable purification of AAV2, AAV4 or AAV5 using ion-exchange chromatography
US20040138163A1 (en) * 2002-05-29 2004-07-15 Mcswiggen James RNA interference mediated inhibition of vascular edothelial growth factor and vascular edothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20040142895A1 (en) * 1995-10-26 2004-07-22 Sirna Therapeutics, Inc. Nucleic acid-based modulation of gene expression in the vascular endothelial growth factor pathway
US20040162255A1 (en) * 2002-11-26 2004-08-19 Medtronic, Inc. Treatment of neurodegenerative disease through intracranial delivery of siRNA
US20040192626A1 (en) * 2002-02-20 2004-09-30 Mcswiggen James RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20040198682A1 (en) * 2001-11-30 2004-10-07 Mcswiggen James RNA interference mediated inhibition of placental growth factor gene expression using short interfering nucleic acid (siNA)
US20040197313A1 (en) * 2003-04-02 2004-10-07 Institute Of Materials Research And Engineering Promoter construct for gene expression in neuronal cells
US20040209831A1 (en) * 2002-02-20 2004-10-21 Mcswiggen James RNA interference mediated inhibition of hepatitis C virus (HCV) gene expression using short interfering nucleic acid (siNA)
US20040219671A1 (en) * 2002-02-20 2004-11-04 Sirna Therapeutics, Inc. RNA interference mediated treatment of parkinson disease using short interfering nucleic acid (siNA)
US20040220132A1 (en) * 2002-11-26 2004-11-04 Medtronic, Inc. Treatment of neurodegenerative disease through intracranial delivery of siRNA
US20040220128A1 (en) * 1995-10-26 2004-11-04 Sirna Therapeutics, Inc. Nucleic acid based modulation of female reproductive diseases and conditions
WO2004098648A1 (fr) 2003-05-01 2004-11-18 Genzyme Corporation Therapie genique pour troubles neurometaboliques
US20040231231A1 (en) * 2002-12-20 2004-11-25 Cataldo Dominic A. Use of colloidal clays for sustained release of active ingredients
US20040258666A1 (en) * 2003-05-01 2004-12-23 Passini Marco A. Gene therapy for neurometabolic disorders
US20050010261A1 (en) * 2002-10-21 2005-01-13 The Cleveland Clinic Foundation Application of stimulus to white matter to induce a desired physiological response
US20050014172A1 (en) * 2002-02-20 2005-01-20 Ivan Richards RNA interference mediated inhibition of muscarinic cholinergic receptor gene expression using short interfering nucleic acid (siNA)
US20050032733A1 (en) * 2001-05-18 2005-02-10 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (SiNA)
US20050031593A1 (en) * 2003-06-03 2005-02-10 Thomas Harding Method for treating cancer by vector-mediated delivery of one or more anti-angiogenic or pro-apoptotic genes
US6855314B1 (en) * 2000-03-22 2005-02-15 The United States Of America As Represented By The Department Of Health And Human Services AAV5 vector for transducing brain cells and lung cells
US20050042632A1 (en) * 2002-02-13 2005-02-24 Sirna Therapeutics, Inc. Antibodies having specificity for nucleic acids
US20050054596A1 (en) * 2001-11-30 2005-03-10 Mcswiggen James RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20050054598A1 (en) * 2002-02-20 2005-03-10 Sirna Therapeutics, Inc. RNA interference mediated inhibition hairless (HR) gene expression using short interfering nucleic acid (siNA)
US20050070493A1 (en) * 2001-10-30 2005-03-31 Fawell Stephen Eric Methods and compositions for treating Parkinson's disease
US20050075304A1 (en) * 2001-11-30 2005-04-07 Mcswiggen James RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20050079610A1 (en) * 2001-05-18 2005-04-14 Sirna Therapeutics, Inc. RNA interference mediated inhibition of Fos gene expression using short interfering nucleic acid (siNA)
US20050080031A1 (en) * 2001-05-18 2005-04-14 Sirna Therapeutics, Inc. Nucleic acid treatment of diseases or conditions related to levels of Ras, HER2 and HIV
US20050096284A1 (en) * 2002-02-20 2005-05-05 Sirna Therapeutics, Inc. RNA interference mediated treatment of polyglutamine (polyQ) repeat expansion diseases using short interfering nucleic acid (siNA)
US20050119211A1 (en) * 2001-05-18 2005-06-02 Sirna Therapeutics, Inc. RNA mediated inhibition connexin gene expression using short interfering nucleic acid (siNA)
US20050119212A1 (en) * 2001-05-18 2005-06-02 Sirna Therapeutics, Inc. RNA interference mediated inhibition of FAS and FASL gene expression using short interfering nucleic acid (siNA)
US20050124567A1 (en) * 2001-05-18 2005-06-09 Sirna Therapeutics, Inc. RNA interference mediated inhibition of TRPM7 gene expression using short interfering nucleic acid (siNA)
US20050124568A1 (en) * 2001-05-18 2005-06-09 Sirna Therapeutics, Inc. RNA interference mediated inhibition of acetyl-CoA-carboxylase gene expression using short interfering nucleic acid (siNA)
US20050124566A1 (en) * 2001-05-18 2005-06-09 Sirna Therapeutics, Inc. RNA interference mediated inhibition of myostatin gene expression using short interfering nucleic acid (siNA)
US20050130181A1 (en) * 2001-05-18 2005-06-16 Sirna Therapeutics, Inc. RNA interference mediated inhibition of wingless gene expression using short interfering nucleic acid (siNA)
US20050137153A1 (en) * 2002-02-20 2005-06-23 Sirna Therapeutics, Inc. RNA interference mediated inhibition of alpha-1 antitrypsin (AAT) gene expression using short interfering nucleic acid (siNA)
US20050137155A1 (en) * 2001-05-18 2005-06-23 Sirna Therapeutics, Inc. RNA interference mediated treatment of Parkinson disease using short interfering nucleic acid (siNA)
US20050136436A1 (en) * 2001-05-18 2005-06-23 Sirna Therapeutics, Inc. RNA interference mediated inhibition of G72 and D-amino acid oxidase (DAAO) gene expression using short interfering nucleic acid (siNA)
US20050143330A1 (en) * 2002-09-30 2005-06-30 Ron Mandel Method for the treatment of Parkinson's Disease
US20050143333A1 (en) * 2001-05-18 2005-06-30 Sirna Therapeutics, Inc. RNA interference mediated inhibition of interleukin and interleukin receptor gene expression using short interfering nucleic acid (SINA)
US20050148530A1 (en) * 2002-02-20 2005-07-07 Sirna Therapeutics, Inc. RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20050153914A1 (en) * 2001-05-18 2005-07-14 Sirna Therapeutics, Inc. RNA interference mediated inhibition of MDR P-glycoprotein gene expression using short interfering nucleic acid (siNA)
US20050153915A1 (en) * 2001-05-18 2005-07-14 Sirna Therapeutics, Inc. RNA interference mediated inhibition of early growth response gene expression using short interfering nucleic acid (siNA)
US20050159382A1 (en) * 2001-05-18 2005-07-21 Sirna Therapeutics, Inc. RNA interference mediated inhibition of polycomb group protein EZH2 gene expression using short interfering nucleic acid (siNA)
US20050159379A1 (en) * 2001-05-18 2005-07-21 Sirna Therapeutics, Inc RNA interference mediated inhibition of gastric inhibitory polypeptide (GIP) and gastric inhibitory polypeptide receptor (GIPR) gene expression using short interfering nucleic acid (siNA)
US20050159376A1 (en) * 2002-02-20 2005-07-21 Slrna Therapeutics, Inc. RNA interference mediated inhibition 5-alpha reductase and androgen receptor gene expression using short interfering nucleic acid (siNA)
US20050159380A1 (en) * 2001-05-18 2005-07-21 Sirna Therapeutics, Inc. RNA interference mediated inhibition of angiopoietin gene expression using short interfering nucleic acid (siNA)
US20050164224A1 (en) * 2001-05-18 2005-07-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of cyclin D1 gene expression using short interfering nucleic acid (siNA)
US20050164967A1 (en) * 2001-05-18 2005-07-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of platelet-derived endothelial cell growth factor (ECGF1) gene expression using short interfering nucleic acid (siNA)
US20050164968A1 (en) * 2001-05-18 2005-07-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of ADAM33 gene expression using short interfering nucleic acid (siNA)
US20050164966A1 (en) * 2001-05-18 2005-07-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of type 1 insulin-like growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20050176665A1 (en) * 2001-05-18 2005-08-11 Sirna Therapeutics, Inc. RNA interference mediated inhibition of hairless (HR) gene expression using short interfering nucleic acid (siNA)
US20050176666A1 (en) * 2001-05-18 2005-08-11 Sirna Therapeutics, Inc. RNA interference mediated inhibition of GPRA and AAA1 gene expression using short interfering nucleic acid (siNA)
US20050176664A1 (en) * 2001-05-18 2005-08-11 Sirna Therapeutics, Inc. RNA interference mediated inhibition of cholinergic muscarinic receptor (CHRM3) gene expression using short interfering nucleic acid (siNA)
US20050182006A1 (en) * 2001-05-18 2005-08-18 Sirna Therapeutics, Inc RNA interference mediated inhibition of protein kinase C alpha (PKC-alpha) gene expression using short interfering nucleic acid (siNA)
US20050182009A1 (en) * 2001-05-18 2005-08-18 Sirna Therapeutics, Inc. RNA interference mediated inhibition of NF-Kappa B / REL-A gene expression using short interfering nucleic acid (siNA)
US20050180955A1 (en) * 1998-05-27 2005-08-18 Regents Of The University Of California Methods of treating parkinson's disease using viral vectors
US20050182007A1 (en) * 2001-05-18 2005-08-18 Sirna Therapeutics, Inc. RNA interference mediated inhibition of interleukin and interleukin receptor gene expression using short interfering nucleic acid (SINA)
US20050187174A1 (en) * 2001-05-18 2005-08-25 Sirna Therapeutics, Inc. RNA interference mediated inhibition of intercellular adhesion molecule (ICAM) gene expression using short interfering nucleic acid (siNA)
US20050191638A1 (en) * 2002-02-20 2005-09-01 Sirna Therapeutics, Inc. RNA interference mediated treatment of polyglutamine (polyQ) repeat expansion diseases using short interfering nucleic acid (siNA)
US20050196767A1 (en) * 2001-05-18 2005-09-08 Sirna Therapeutics, Inc. RNA interference mediated inhibition of GRB2 associated binding protein (GAB2) gene expression using short interfering nucleic acis (siNA)
US20050196765A1 (en) * 2001-05-18 2005-09-08 Sirna Therapeutics, Inc. RNA interference mediated inhibition of checkpoint Kinase-1 (CHK-1) gene expression using short interfering nucleic acid (siNA)
US20050203040A1 (en) * 2001-05-18 2005-09-15 Sirna Therapeutics, Inc. RNA interference mediated inhibition of vascular cell adhesion molecule (VCAM) gene expression using short interfering nucleic acid (siNA)
US20050209180A1 (en) * 2001-05-18 2005-09-22 Sirna Therapeutics, Inc. RNA interference mediated inhibition of hepatitis C virus (HCV) expression using short interfering nucleic acid (siNA)
US20050208032A1 (en) * 2004-01-16 2005-09-22 Gonzalo Hortelano Oral administration of therapeutic agent coupled to transporting agent
US20050209179A1 (en) * 2000-08-30 2005-09-22 Sirna Therapeutics, Inc. RNA interference mediated treatment of Alzheimer's disease using short interfering nucleic acid (siNA)
US20050222066A1 (en) * 2001-05-18 2005-10-06 Sirna Therapeutics, Inc. RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20050222064A1 (en) * 2002-02-20 2005-10-06 Sirna Therapeutics, Inc. Polycationic compositions for cellular delivery of polynucleotides
US20050227935A1 (en) * 2001-05-18 2005-10-13 Sirna Therapeutics, Inc. RNA interference mediated inhibition of TNF and TNF receptor gene expression using short interfering nucleic acid (siNA)
US20050233344A1 (en) * 2001-05-18 2005-10-20 Sirna Therapeutics, Inc. RNA interference mediated inhibition of platelet derived growth factor (PDGF) and platelet derived growth factor receptor (PDGFR) gene expression using short interfering nucleic acid (siNA)
US20050233996A1 (en) * 2002-02-20 2005-10-20 Sirna Therapeutics, Inc. RNA interference mediated inhibition of hairless (HR) gene expression using short interfering nucleic acid (siNA)
US20050233997A1 (en) * 2001-05-18 2005-10-20 Sirna Therapeutics, Inc. RNA interference mediated inhibition of matrix metalloproteinase 13 (MMP13) gene expression using short interfering nucleic acid (siNA)
US20050233990A1 (en) * 2001-08-29 2005-10-20 Yong-Serk Park Anti-cancer agents comprising disintegrin genes and the treating methods
US20050255089A1 (en) * 1998-05-28 2005-11-17 Chiorini John A AAV5 nucleic acids
US20050256068A1 (en) * 2001-05-18 2005-11-17 Sirna Therapeutics, Inc. RNA interference mediated inhibition of stearoyl-CoA desaturase (SCD) gene expression using short interfering nucleic acid (siNA)
US20050267058A1 (en) * 2001-05-18 2005-12-01 Sirna Therapeutics, Inc. RNA interference mediated inhibition of placental growth factor gene expression using short interfering nucleic acid (sINA)
US20050282188A1 (en) * 2001-05-18 2005-12-22 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA)
US20050281786A1 (en) * 2004-06-18 2005-12-22 David Poulsen AAV mediated gene delivery to cochlear cells
US20050287128A1 (en) * 2001-05-18 2005-12-29 Sirna Therapeutics, Inc. RNA interference mediated inhibition of TGF-beta and TGF-beta receptor gene expression using short interfering nucleic acid (siNA)
US20050288242A1 (en) * 2001-05-18 2005-12-29 Sirna Therapeutics, Inc. RNA interference mediated inhibition of RAS gene expression using short interfering nucleic acid (siNA)
US20060019913A1 (en) * 2001-05-18 2006-01-26 Sirna Therapeutics, Inc. RNA interference mediated inhibtion of protein tyrosine phosphatase-1B (PTP-1B) gene expression using short interfering nucleic acid (siNA)
US20060142226A1 (en) * 2001-05-18 2006-06-29 Sirna Therapeutics, Inc. RNA interference mediated inhibition of cholesteryl ester transfer protein (CETP) gene expression using short interfering nucleic acid (siNA)
US20060142225A1 (en) * 2001-05-18 2006-06-29 Sirna Therapeutics, Inc. RNA interference mediated inhibition of cyclin dependent kinase-2 (CDK2) gene expression using short interfering nucleic acid (siNA)
US20060171926A1 (en) * 2004-04-30 2006-08-03 Passini Marco A Gene therapy for neurometabolic disorders
US20060178328A1 (en) * 2002-11-26 2006-08-10 Medtronic Inc. Devices, systems and methods for improving memory and/or cognitive function through brain delivery of siRNA
US20060211642A1 (en) * 2001-05-18 2006-09-21 Sirna Therapeutics, Inc. RNA inteference mediated inhibition of hepatitis C virus (HVC) gene expression using short interfering nucleic acid (siNA)
US20060217332A1 (en) * 2001-05-18 2006-09-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20060217330A1 (en) * 2004-12-09 2006-09-28 Gunther Hartmann Compositions and methods for inducing an immune response in a mammal and methods of avoiding an immune response to oligonucleotide agents such as short interfering RNAs
US20060241075A1 (en) * 2001-05-18 2006-10-26 Sirna Therapeutics, Inc. RNA interference mediated inhibition of desmoglein gene expression using short interfering nucleic acid (siNA)
US20060239966A1 (en) * 2003-10-20 2006-10-26 Tornoee Jens In vivo gene therapy of parkinson's disease
US20060253068A1 (en) * 2005-04-20 2006-11-09 Van Bilsen Paul Use of biocompatible in-situ matrices for delivery of therapeutic cells to the heart
US20070072282A1 (en) * 2003-12-04 2007-03-29 Chiorini John A Bovine adeno-associated viral (baav) vector and uses thereof
WO2007008486A3 (fr) * 2005-07-07 2007-06-07 Genzyme Corp Vecteurs de aav codant pour la superoxyde dismutase
US20070148132A1 (en) * 2004-05-18 2007-06-28 Bohn Martha C Tetracycline-regulated adeno-associated viral (AAV) vectors for gene delivery to the nervous system
US20070160980A1 (en) * 2001-05-18 2007-07-12 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA)
US20070167389A1 (en) * 2003-11-25 2007-07-19 Kaemmerer William F Compositions, devices and methods for treatment of huntington's disease through intracranial delivery of sirna
US20070203333A1 (en) * 2001-11-30 2007-08-30 Mcswiggen James RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20070254842A1 (en) * 2006-04-25 2007-11-01 The Regents Of The University Of California Administration of growth factors for the treatment of cns disorders
US20070259031A1 (en) * 2006-04-26 2007-11-08 The Regents Of The University Of California Compositions and methods for convection enhanced delivery of high molecular weight neurotherapeutics
US20070261126A1 (en) * 2005-05-06 2007-11-08 Kaemmerer William F Methods and sequences to suppress primate huntington gene expression in vivo
WO2007092563A3 (fr) * 2006-02-08 2007-11-22 Genzyme Corp Therapie genique destinee a la maladie de niemann-pick de type a
US20070270579A1 (en) * 2001-05-18 2007-11-22 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA)
WO2007146046A2 (fr) 2006-06-07 2007-12-21 Genzyme Corporation Thérapie génique destinée à traiter la sclérose latérale amyotrophique et d'autres troubles de la moelle épinière
US20080032942A1 (en) * 2000-08-30 2008-02-07 Mcswiggen James RNA interference mediated treatment of Alzheimer's disease using short interfering nucleic acid (siNA)
US20080039414A1 (en) * 2002-02-20 2008-02-14 Sima Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20080039415A1 (en) * 2006-08-11 2008-02-14 Gregory Robert Stewart Retrograde transport of sirna and therapeutic uses to treat neurologic disorders
US20080051358A1 (en) * 1997-09-16 2008-02-28 New Jersey University Of Med. And Dentistry Of New Jersey Novel human lysosomal protein and methods of its use
US20080119787A1 (en) * 2006-11-21 2008-05-22 Kaemmerer William F Microsyringe for pre-packaged delivery of pharmaceuticals
US20080119789A1 (en) * 2006-11-21 2008-05-22 Kaemmerer William F Chronically implantable guide tube for repeated intermittent delivery of materials or fluids to targeted tissue sites
US20080124379A1 (en) * 2006-11-03 2008-05-29 Kaemmerer William F Compositions and methods for making therapies delivered by viral vectors reversible for safety and allele-specificity
US20080161256A1 (en) * 2001-05-18 2008-07-03 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA)
US20080171906A1 (en) * 2007-01-16 2008-07-17 Everaerts Frank J L Tissue performance via hydrolysis and cross-linking
US20080188431A1 (en) * 2004-09-08 2008-08-07 Chiorini John A Transcytosis of Adeno-Associated Viruses
US20080188430A1 (en) * 2001-05-18 2008-08-07 Sirna Therapeutics, Inc. RNA interference mediated inhibition of hypoxia inducible factor 1 (HIF1) gene expression using short interfering nucleic acid (siNA)
US20080280843A1 (en) * 2006-05-24 2008-11-13 Van Bilsen Paul Methods and kits for linking polymorphic sequences to expanded repeat mutations
WO2008154198A1 (fr) 2007-06-06 2008-12-18 Genzyme Corporation Thérapie génique pour les maladies de stockage lysosomal
US20090022667A1 (en) * 2007-05-15 2009-01-22 Marco Peters METHODS OF TREATING COGNITIVE DISORDERS BY INHIBITION OF Gpr12
US20090069261A1 (en) * 2005-05-02 2009-03-12 Genzyme Corporation Gene therapy for spinal cord disorders
US20090137500A1 (en) * 2002-02-20 2009-05-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20090176725A1 (en) * 2005-08-17 2009-07-09 Sirna Therapeutics Inc. Chemically modified short interfering nucleic acid molecules that mediate rna interference
WO2009123764A2 (fr) 2008-04-04 2009-10-08 Calando Pharmaceuticals, Inc. Compositions et utilisation d'inhibiteurs d'epas1
US20100008981A1 (en) * 2005-05-06 2010-01-14 Medtronic, Inc. Methods and sequences to suppress primate huntington gene expression
EP2181704A2 (fr) 2002-12-30 2010-05-05 Angiotech International Ag Liberation de medicaments a partir d'une compostion polymere a gelification rapide
US20100120900A1 (en) * 2005-06-28 2010-05-13 Medtronic, Inc. Methods And Sequences To Preferentially Suppress Expression of Mutated Huntingtin
US20100129405A1 (en) * 2005-04-29 2010-05-27 Michael Schmidt Isolation, cloning and characterization of new adeno-associated virus (aav) serotypes
WO2010071454A1 (fr) * 2008-12-17 2010-06-24 Auckland Uniservices Limited Vecteurs viraux adéno-associés et leurs utilisations
EP2210617A1 (fr) 2003-10-20 2010-07-28 NsGene A/S Cellules mammifères sécrétant de la neurturine et leur usage thérapeutique
WO2010083842A2 (fr) 2009-01-23 2010-07-29 Nsgene A/S Expression de neuropeptides dans des cellules mammaliennes
US20100240441A1 (en) * 2007-09-14 2010-09-23 Konami Digital Entertainment Co., Ltd Game system, and game apparatus and challenge notifying apparatus constituting the game system
US20100256065A1 (en) * 2006-03-30 2010-10-07 Research Foundation Of City University Of New York Stimulation of neuron regeneration by secretory leukocyte protease inhibitor
US20110059041A1 (en) * 2003-09-12 2011-03-10 Alemseged Truneh Vaccine for treatment and prevention of herpes simplex virus infection
US7923547B2 (en) 2002-09-05 2011-04-12 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20110178157A1 (en) * 2009-12-09 2011-07-21 Nitto Denko Technical Corporation Modulation of hsp47 expression
EP2360249A1 (fr) 2005-03-31 2011-08-24 Calando Pharmaceuticals, Inc. Inhibiteurs de la sous-unite 2 de la ribonucleotide reductase et utilisations associees
US20110213328A1 (en) * 2004-03-18 2011-09-01 Medtronic, Inc. Methods and Systems for Treatment of Neurological Diseases of the Central Nervous System
WO2011163436A1 (fr) 2010-06-24 2011-12-29 Quark Pharmaceuticals, Inc. Composés à base d'arn double brin pour le gène rhoa et leur utilisation
EP2420256A1 (fr) 2005-05-02 2012-02-22 Genzyme Corporation Thérapie génique pour les troubles neurométaboliques
EP2497500A1 (fr) 2006-10-03 2012-09-12 Genzyme Corporation Thérapie génique pour la sclérose latérale amyotrophique et autres troubles de la moelle épinière
US8324367B2 (en) 2006-11-03 2012-12-04 Medtronic, Inc. Compositions and methods for making therapies delivered by viral vectors reversible for safety and allele-specificity
WO2012170952A2 (fr) 2011-06-08 2012-12-13 Nitto Denko Corporation Composés pour l'administration de médicament ciblée et l'augmentation de l'activité arnsi
WO2012170957A2 (fr) 2011-06-08 2012-12-13 Nitto Denko Corporation Liposomes-rétinoïdes permettant d'améliorer la modulation de l'expression de hsp47
US8927269B2 (en) 2003-05-19 2015-01-06 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Avian adenoassociated virus and uses thereof
US8957198B2 (en) 2003-02-03 2015-02-17 Medtronic, Inc. Compositions, devices and methods for treatment of Huntington's disease through intracranial delivery of sirna
US9011903B2 (en) 2011-06-08 2015-04-21 Nitto Denko Corporation Cationic lipids for therapeutic agent delivery formulations
US20150165227A1 (en) * 2005-07-22 2015-06-18 The Board Of Trustees Of The Leland Stanford Junior University Light-Activated Cation Channel and Uses Thereof
US9181551B2 (en) 2002-02-20 2015-11-10 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US9260471B2 (en) 2010-10-29 2016-02-16 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acids (siNA)
US9273356B2 (en) 2006-05-24 2016-03-01 Medtronic, Inc. Methods and kits for linking polymorphic sequences to expanded repeat mutations
EP3000320A1 (fr) 2007-05-16 2016-03-30 The Brigham and Women's Hospital, Inc. Traitement de synucléinopathies
US9394347B2 (en) 2008-04-23 2016-07-19 The Board Of Trustees Of The Leland Stanford Junior University Methods for treating parkinson's disease by optically stimulating target cells
US9453215B2 (en) 2008-05-29 2016-09-27 The Board Of Trustees Of The Leland Stanford Junior University Cell line, system and method for optical control of secondary messengers
US9458208B2 (en) 2008-11-14 2016-10-04 The Board Of Trustees Of The Leland Stanford Junior University Optically-based stimulation of target cells and modifications thereto
WO2016164642A1 (fr) 2015-04-08 2016-10-13 The United States Of America, As Represented By The Secretary Of Health And Human Services Thérapie génique virale à utiliser en tant que traitement pour une maladie ou un trouble associé au stockage du cholestérol
WO2016179497A1 (fr) 2015-05-07 2016-11-10 Shire Human Genetic Therapies, Inc. Thérapie génique par glucocérébrosidase pour la maladie de parkinson
US9505817B2 (en) 2011-12-16 2016-11-29 The Board Of Trustees Of The Leland Stanford Junior University Opsin polypeptides and methods of use thereof
US9522288B2 (en) 2010-11-05 2016-12-20 The Board Of Trustees Of The Leland Stanford Junior University Upconversion of light for use in optogenetic methods
US9604073B2 (en) 2010-03-17 2017-03-28 The Board Of Trustees Of The Leland Stanford Junior University Light-sensitive ion-passing molecules
US9615789B2 (en) 2010-11-22 2017-04-11 The Board Of Trustees Of The Leland Stanford Junior University Optogenetic magnetic resonance imaging
US9636380B2 (en) 2013-03-15 2017-05-02 The Board Of Trustees Of The Leland Stanford Junior University Optogenetic control of inputs to the ventral tegmental area
WO2017075335A1 (fr) 2015-10-28 2017-05-04 Voyager Therapeutics, Inc. Expression régulable au moyen d'un virus adéno-associé (vaa)
US9657294B2 (en) 2002-02-20 2017-05-23 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US9693692B2 (en) 2007-02-14 2017-07-04 The Board Of Trustees Of The Leland Stanford Junior University System, method and applications involving identification of biological circuits such as neurological characteristics
US9757587B2 (en) 2007-03-01 2017-09-12 The Board Of Trustees Of The Leland Stanford Junior University Optogenetic method for generating an inhibitory current in a mammalian neuron
US9850290B2 (en) 2010-11-05 2017-12-26 The Board Of Trustees Of The Leland Stanford Junior University Light-activated chimeric opsins and methods of using the same
US9968652B2 (en) 2010-11-05 2018-05-15 The Board Of Trustees Of The Leland Stanford Junior University Optically-controlled CNS dysfunction
US9994853B2 (en) 2001-05-18 2018-06-12 Sirna Therapeutics, Inc. Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference
US9992981B2 (en) 2010-11-05 2018-06-12 The Board Of Trustees Of The Leland Stanford Junior University Optogenetic control of reward-related behaviors
US10016514B2 (en) 2015-05-15 2018-07-10 New Hope Research Foundation Polynucleotides, vectors and methods for insertion and expression of transgenes
US10035027B2 (en) 2007-10-31 2018-07-31 The Board Of Trustees Of The Leland Stanford Junior University Device and method for ultrasonic neuromodulation via stereotactic frame based technique
US10046174B2 (en) 2005-07-22 2018-08-14 The Board Of Trustees Of The Leland Stanford Junior University System for electrically stimulating target neuronal cells of a living animal in vivo
US10052497B2 (en) 2005-07-22 2018-08-21 The Board Of Trustees Of The Leland Stanford Junior University System for optical stimulation of target cells
US10086012B2 (en) 2010-11-05 2018-10-02 The Board Of Trustees Of The Leland Stanford Junior University Control and characterization of memory function
US10105551B2 (en) 2007-01-10 2018-10-23 The Board Of Trustees Of The Leland Stanford Junior University System for optical stimulation of target cells
US20180362592A1 (en) * 2009-05-28 2018-12-20 University Of Massachusetts Novel aav's and uses thereof
WO2018237066A1 (fr) 2017-06-20 2018-12-27 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Gènes npc1 humains optimisés par des codons pour le traitement d'une maladie de niemann-pick de type c1 et d'états associés
US10196637B2 (en) 2011-06-08 2019-02-05 Nitto Denko Corporation Retinoid-lipid drug carrier
WO2019028306A2 (fr) 2017-08-03 2019-02-07 Voyager Therapeutics, Inc. Compositions et procédés permettant l'administration de virus adéno-associés
US10220092B2 (en) 2013-04-29 2019-03-05 The Board Of Trustees Of The Leland Stanford Junior University Devices, systems and methods for optogenetic modulation of action potentials in target cells
WO2019079242A1 (fr) 2017-10-16 2019-04-25 Voyager Therapeutics, Inc. Traitement de la sclérose latérale amyotrophique (sla)
WO2019079240A1 (fr) 2017-10-16 2019-04-25 Voyager Therapeutics, Inc. Traitement de la sclérose latérale amyotrophique (sla)
US10287608B2 (en) 2017-04-03 2019-05-14 Encoded Therapeutics, Inc. Tissue selective transgene expression
US10307609B2 (en) 2013-08-14 2019-06-04 The Board Of Trustees Of The Leland Stanford Junior University Compositions and methods for controlling pain
EP3492593A1 (fr) 2013-11-13 2019-06-05 Children's Medical Center Corporation Régulation de l'expression génique médiée par la nucléase
US10335466B2 (en) 2014-11-05 2019-07-02 Voyager Therapeutics, Inc. AADC polynucleotides for the treatment of parkinson's disease
WO2019173434A1 (fr) 2018-03-06 2019-09-12 Voyager Therapeutics, Inc. Génomes aav partiels auto-complémentaires fabriqués par des cellules d'insectes
US10426970B2 (en) 2007-10-31 2019-10-01 The Board Of Trustees Of The Leland Stanford Junior University Implantable optical stimulators
US10451608B2 (en) 2005-07-22 2019-10-22 The Board Of Trustees Of The Leland Stanford Junior University Cell line, system and method for optical-based screening of ion-channel modulators
WO2019222329A1 (fr) 2018-05-15 2019-11-21 Voyager Therapeutics, Inc. Compositions et procédés pour l'administration de vaa
WO2019222444A2 (fr) 2018-05-16 2019-11-21 Voyager Therapeutics, Inc. Évolution dirigée
WO2019222441A1 (fr) 2018-05-16 2019-11-21 Voyager Therapeutics, Inc. Sérotypes de vaa pour l'administration de charge utile spécifique au cerveau
US10508277B2 (en) 2004-05-24 2019-12-17 Sirna Therapeutics, Inc. Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference
WO2019241486A1 (fr) 2018-06-13 2019-12-19 Voyager Therapeutics, Inc. Régions 5' non traduites (5'utr) modifiées pour la production d'aav
WO2020010042A1 (fr) 2018-07-02 2020-01-09 Voyager Therapeutics, Inc. Traitement de la sclérose latérale amyotrophique et de troubles associés à la moelle épinière
WO2020010035A1 (fr) 2018-07-02 2020-01-09 Voyager Therapeutics, Inc. Système de canule
WO2020023612A1 (fr) 2018-07-24 2020-01-30 Voyager Therapeutics, Inc. Systèmes et méthodes de production de formulations de thérapie génique
US10568307B2 (en) 2010-11-05 2020-02-25 The Board Of Trustees Of The Leland Stanford Junior University Stabilized step function opsin proteins and methods of using the same
US10569099B2 (en) 2005-07-22 2020-02-25 The Board Of Trustees Of The Leland Stanford Junior University System for optical stimulation of target cells
US10568516B2 (en) 2015-06-22 2020-02-25 The Board Of Trustees Of The Leland Stanford Junior University Methods and devices for imaging and/or optogenetic control of light-responsive neurons
US10570395B2 (en) 2014-11-14 2020-02-25 Voyager Therapeutics, Inc. Modulatory polynucleotides
US10577627B2 (en) 2014-06-09 2020-03-03 Voyager Therapeutics, Inc. Chimeric capsids
US10584337B2 (en) 2016-05-18 2020-03-10 Voyager Therapeutics, Inc. Modulatory polynucleotides
US10583309B2 (en) 2008-07-08 2020-03-10 The Board Of Trustees Of The Leland Stanford Junior University Materials and approaches for optical stimulation of the peripheral nervous system
US10597660B2 (en) 2014-11-14 2020-03-24 Voyager Therapeutics, Inc. Compositions and methods of treating amyotrophic lateral sclerosis (ALS)
WO2020069461A1 (fr) 2018-09-28 2020-04-02 Voyager Therapeutics, Inc. Constructions d'expression de frataxine comprenant des promoteurs modifiés et leurs méthodes d'utilisation
US10610606B2 (en) 2018-02-01 2020-04-07 Homology Medicines, Inc. Adeno-associated virus compositions for PAH gene transfer and methods of use thereof
WO2020072849A1 (fr) 2018-10-04 2020-04-09 Voyager Therapeutics, Inc. Procédés de mesure du titre et de la puissance de particules de vecteur viral
WO2020072844A1 (fr) 2018-10-05 2020-04-09 Voyager Therapeutics, Inc. Constructions d'acides nucléiques modifiés codant pour des protéines de production d'aav
WO2020077165A1 (fr) 2018-10-12 2020-04-16 Voyager Therapeutics, Inc. Compositions et procédés pour l'administration d'aav
WO2020081490A1 (fr) 2018-10-15 2020-04-23 Voyager Therapeutics, Inc. Vecteurs d'expression pour la production à grande échelle de raav dans le système baculovirus/sf9
US10711242B2 (en) 2008-06-17 2020-07-14 The Board Of Trustees Of The Leland Stanford Junior University Apparatus and methods for controlling cellular development
WO2020150556A1 (fr) 2019-01-18 2020-07-23 Voyager Therapeutics, Inc. Procédés et systèmes de fabrication de particules aav
US10731178B2 (en) 2010-04-23 2020-08-04 University Of Massachusetts CNS targeting AAV vectors and methods of use thereof
WO2020223274A1 (fr) 2019-04-29 2020-11-05 Voyager Therapeutics, Inc. Système et procédé pour la production de cellules d'insectes infectées par baculovirus (ceib) dans les bioréacteurs
WO2021030125A1 (fr) 2019-08-09 2021-02-18 Voyager Therapeutics, Inc. Milieu de culture cellulaire destiné à être utilisé dans la production de produits de thérapie génique dans des bioréacteurs
WO2021041485A1 (fr) 2019-08-26 2021-03-04 Voyager Therapeutics, Inc. Expression contrôlée de protéines virales
US10974064B2 (en) 2013-03-15 2021-04-13 The Board Of Trustees Of The Leland Stanford Junior University Optogenetic control of behavioral state
US11103723B2 (en) 2012-02-21 2021-08-31 The Board Of Trustees Of The Leland Stanford Junior University Methods for treating neurogenic disorders of the pelvic floor
WO2021247995A2 (fr) 2020-06-04 2021-12-09 Voyager Therapeutics, Inc. Compositions et méthodes de traitement de la douleur neuropathique
WO2022017630A1 (fr) 2020-07-23 2022-01-27 Ucl Business Ltd Vecteur de thérapie génique pour eef1a2 et ses utilisations
WO2022026410A2 (fr) 2020-07-27 2022-02-03 Voyager Therapeutics, Inc Compositions et méthodes pour le traitement de la maladie de niemann-pick de type c1
WO2022026409A1 (fr) 2020-07-27 2022-02-03 Voyager Therapeutics, Inc. Compositions et procédés pour le traitement des troubles neurologiques liés au déficit en glucosylcéramidase bêta
WO2022032153A1 (fr) 2020-08-06 2022-02-10 Voyager Therapeutics, Inc. Milieu de culture cellulaire destiné à être utilisé dans la production de produits de thérapie génique dans des bioréacteurs
US11294165B2 (en) 2017-03-30 2022-04-05 The Board Of Trustees Of The Leland Stanford Junior University Modular, electro-optical device for increasing the imaging field of view using time-sequential capture
US11299751B2 (en) 2016-04-29 2022-04-12 Voyager Therapeutics, Inc. Compositions for the treatment of disease
US11298041B2 (en) 2016-08-30 2022-04-12 The Regents Of The University Of California Methods for biomedical targeting and delivery and devices and systems for practicing the same
US11306329B2 (en) 2018-02-19 2022-04-19 City Of Hope Adeno-associated virus compositions for restoring F8 gene function and methods of use thereof
US11326182B2 (en) 2016-04-29 2022-05-10 Voyager Therapeutics, Inc. Compositions for the treatment of disease
WO2022187473A2 (fr) 2021-03-03 2022-09-09 Voyager Therapeutics, Inc. Expression contrôlée de protéines virales
WO2022187548A1 (fr) 2021-03-03 2022-09-09 Voyager Therapeutics, Inc. Expression régulée de protéines virales
US11497576B2 (en) 2017-07-17 2022-11-15 Voyager Therapeutics, Inc. Trajectory array guide system
US11542525B2 (en) 2014-10-21 2023-01-03 University Of Massachusetts Recombinant AAV variants and uses thereof
US11578340B2 (en) 2016-10-13 2023-02-14 University Of Massachusetts AAV capsid designs
US11603542B2 (en) 2017-05-05 2023-03-14 Voyager Therapeutics, Inc. Compositions and methods of treating amyotrophic lateral sclerosis (ALS)
WO2023092004A1 (fr) 2021-11-17 2023-05-25 Voyager Therapeutics, Inc. Compositions et méthodes pour le traitement de troubles liés à tau
WO2023091949A2 (fr) 2021-11-17 2023-05-25 Voyager Therapeutics, Inc. Compositions et méthodes de traitement de troubles neurologiques liés à un déficit en bêta glucosylcéramidase
US11697825B2 (en) 2014-12-12 2023-07-11 Voyager Therapeutics, Inc. Compositions and methods for the production of scAAV
US11752181B2 (en) 2017-05-05 2023-09-12 Voyager Therapeutics, Inc. Compositions and methods of treating Huntington's disease
US11759506B2 (en) 2017-06-15 2023-09-19 Voyager Therapeutics, Inc. AADC polynucleotides for the treatment of Parkinson's disease
US11905523B2 (en) 2019-10-17 2024-02-20 Ginkgo Bioworks, Inc. Adeno-associated viral vectors for treatment of Niemann-Pick Disease type-C
WO2024054983A1 (fr) 2022-09-08 2024-03-14 Voyager Therapeutics, Inc. Expression controlée de protéines virales
US11952585B2 (en) 2020-01-13 2024-04-09 Homology Medicines, Inc. Methods of treating phenylketonuria
US11951121B2 (en) 2016-05-18 2024-04-09 Voyager Therapeutics, Inc. Compositions and methods for treating Huntington's disease
US11976096B2 (en) 2018-04-03 2024-05-07 Ginkgo Bioworks, Inc. Antibody-evading virus vectors
US11981914B2 (en) 2019-03-21 2024-05-14 Ginkgo Bioworks, Inc. Recombinant adeno-associated virus vectors
WO2024140306A1 (fr) * 2022-12-26 2024-07-04 科辉智药(深圳)新药研究中心有限公司 Structure de séquence génique pour le traitement de maladies du système nerveux central et son utilisation
WO2024145474A2 (fr) 2022-12-29 2024-07-04 Voyager Therapeutics, Inc. Compositions et procédés de régulation de mapt
WO2024161032A1 (fr) 2023-02-03 2024-08-08 Janssen Pharmaceutica Nv Vecteurs de thérapie génique pour le traitement de la maladie de parkinson
WO2024163737A1 (fr) 2023-02-02 2024-08-08 Voyager Therapeutics, Inc. Compositions et méthodes pour le traitement de troubles neurologiques liés à une déficience en glucosylcéramidase bêta 1
US12060390B2 (en) 2018-04-03 2024-08-13 Ginkgo Bioworks, Inc. Antibody-evading virus vectors
US12076420B2 (en) 2020-05-27 2024-09-03 Homology Medicines, Inc. Adeno-associated virus compositions for restoring PAH gene function and methods of use thereof
US12083188B2 (en) 2017-12-01 2024-09-10 Encoded Therapeutics, Inc. Engineered DNA binding proteins
US12104163B2 (en) 2020-08-19 2024-10-01 Sarepta Therapeutics, Inc. Adeno-associated virus vectors for treatment of Rett syndrome
US12116384B2 (en) 2018-04-03 2024-10-15 Ginkgo Bioworks, Inc. Virus vectors for targeting ophthalmic tissues
WO2024226761A2 (fr) 2023-04-26 2024-10-31 Voyager Therapeutics, Inc. Compositions et méthodes de traitement de la sclérose latérale amyotrophique
US12146150B2 (en) 2022-09-13 2024-11-19 Voyager Therapeutics, Inc. Rescue of central and peripheral neurological phenotype of friedreich's ataxia by intravenous delivery

Families Citing this family (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5856152A (en) * 1994-10-28 1999-01-05 The Trustees Of The University Of Pennsylvania Hybrid adenovirus-AAV vector and methods of use therefor
WO1997018319A1 (fr) * 1995-11-14 1997-05-22 Somatix Therapy Corporation Expression conjointe de la gtp-cyclohydrolase et de la tyrosine-hydroxylase
US5846528A (en) 1996-01-18 1998-12-08 Avigen, Inc. Treating anemia using recombinant adeno-associated virus virions comprising an EPO DNA sequence
US5962313A (en) 1996-01-18 1999-10-05 Avigen, Inc. Adeno-associated virus vectors comprising a gene encoding a lyosomal enzyme
US5858351A (en) * 1996-01-18 1999-01-12 Avigen, Inc. Methods for delivering DNA to muscle cells using recombinant adeno-associated virus vectors
US20020037867A1 (en) * 1999-02-26 2002-03-28 James M. Wilson Method for recombinant adeno-associated virus-directed gene therapy
US5866552A (en) * 1996-09-06 1999-02-02 The Trustees Of The University Of Pennsylvania Method for expressing a gene in the absence of an immune response
GB2333527B (en) * 1996-10-29 2001-05-02 Oxford Biomedica Ltd Therapeutic gene
US6924123B2 (en) 1996-10-29 2005-08-02 Oxford Biomedica (Uk) Limited Lentiviral LTR-deleted vector
GB9622500D0 (en) * 1996-10-29 1997-01-08 Oxford Biomedica Ltd Therapeutic gene
US6251677B1 (en) 1997-08-25 2001-06-26 The Trustees Of The University Of Pennsylvania Hybrid adenovirus-AAV virus and methods of use thereof
EP1621625B1 (fr) * 1998-05-27 2009-05-13 Genzyme Corporation Vecteurs AAV pour la fabrication des médicaments pour l'administration amélioré par la convection
US6759237B1 (en) 1998-11-05 2004-07-06 The Trustees Of The University Of Pennsylvania Adeno-associated virus serotype 1 nucleic acid sequences, vectors and host cells containing same
AU780231B2 (en) 1998-11-10 2005-03-10 University Of North Carolina At Chapel Hill, The Virus vectors and methods of making and administering the same
WO2000043039A1 (fr) * 1999-01-22 2000-07-27 Matthew John During Traitement de troubles psychologiques a base de vaccin
US6387368B1 (en) 1999-02-08 2002-05-14 The Trustees Of The University Of Pennsylvania Hybrid adenovirus-AAV virus and methods of use thereof
CA2367648A1 (fr) * 1999-03-15 2000-09-21 Xiaoping Qi Transfert de genes par virus adeno-associe recombine influant sur la demyelinisation
EP1916258B1 (fr) 1999-08-09 2014-04-23 Targeted Genetics Corporation Améliorations de l'expression d'une séquence de nucléotides hétérologues à brin unique à partir de vecteurs viraux recombinants par la désignation de la séquence de manière à ce qu'elle forme des paires de bases intrabrins
US6780639B1 (en) 1999-08-24 2004-08-24 Universite Libre De Bruxelles Antibiotic inducible/repressible genetic construct for gene therapy or gene immunization
EP1083227A1 (fr) * 1999-08-24 2001-03-14 Universite Libre De Bruxelles Structure génétique inductible/repressible par antibiotique pour la thérapie génique ou l'immunisation génique
FR2823975B1 (fr) * 2001-04-27 2003-05-30 Sanofi Synthelabo Nouvelle utilisation de pyridoindolone
US20030050273A1 (en) * 2001-08-29 2003-03-13 Keiya Ozawa Compositions and methods for treating neurodegenerative diseases
US7456193B2 (en) * 2002-10-23 2008-11-25 Sanofi-Aventis Pyridoindolone derivatives substituted in the 3-position by a heterocyclic group, their preparation and their application in therapeutics
FR2846329B1 (fr) 2002-10-23 2004-12-03 Sanofi Synthelabo Derives de pyridoindolone substitues en -3 par un phenyle, leur preparation et leur application en therapeutique
FR2869316B1 (fr) 2004-04-21 2006-06-02 Sanofi Synthelabo Derives de pyridoindolone substitues en -6, leur preparation et leur application en therapeutique.
JP5136766B2 (ja) 2004-12-15 2013-02-06 ユニバーシティ オブ ノース カロライナ アット チャペル ヒル キメラベクター
US20090055941A1 (en) * 2005-03-22 2009-02-26 Agency For Science, Technology And Research Novel Neural Cell Specific Promoter And Baculovirus And Method For Gene Delivery
FR2892416B1 (fr) * 2005-10-20 2008-06-27 Sanofi Aventis Sa Derives de 6-heteroarylpyridoindolone, leur preparation et leur application en therapeutique
CA2704786C (fr) * 2007-11-02 2019-04-09 Cornell University Materiaux et procedes associes a une therapie genique de troubles psychiatriques
WO2010093784A2 (fr) 2009-02-11 2010-08-19 The University Of North Carolina At Chapel Hill Vecteurs viraux modifiés et procédés de fabrication et d'utilisation de ceux-ci
SG175409A1 (en) 2009-05-02 2011-12-29 Genzyme Corp Gene therapy for neurodegenerative disorders
CN107828820B (zh) 2010-10-27 2022-06-07 学校法人自治医科大学 用于向神经系统细胞导入基因的腺相关病毒粒子
US10815285B2 (en) * 2011-07-01 2020-10-27 University Of South Florida Recombinant adeno-associated virus-mediated expression of fractalkine for treatment of neuroinflammatory and neurodegenerative diseases
WO2013082458A1 (fr) 2011-12-02 2013-06-06 The Regents Of The University Of California Solution de protection de reperfusion et ses utilisations
EP2900686B1 (fr) 2012-09-28 2020-06-10 The University of North Carolina At Chapel Hill Vecteurs vaa ciblés sur des oligodendrocytes
WO2018191450A2 (fr) 2017-04-14 2018-10-18 National Taiwan University Hospital Thérapie génique pour une carence en aadc
TW201905200A (zh) * 2017-05-05 2019-02-01 美商航海家醫療公司 調節多核苷酸
CN109971729B (zh) * 2019-04-19 2021-07-16 上海信致医药科技有限公司 一种酶组合物

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4797368A (en) * 1985-03-15 1989-01-10 The United States Of America As Represented By The Department Of Health And Human Services Adeno-associated virus as eukaryotic expression vector
US5139941A (en) * 1985-10-31 1992-08-18 University Of Florida Research Foundation, Inc. AAV transduction vectors
US5173414A (en) * 1990-10-30 1992-12-22 Applied Immune Sciences, Inc. Production of recombinant adeno-associated virus vectors
US5252479A (en) * 1991-11-08 1993-10-12 Research Corporation Technologies, Inc. Safe vector for gene therapy
WO1994013788A1 (fr) 1992-12-04 1994-06-23 University Of Pittsburgh Systeme porteur viral de recombinaison
WO1995013365A1 (fr) 1993-11-09 1995-05-18 Targeted Genetics Corporation Production de titres eleves de vecteurs d'aav recombinants
WO1995013391A1 (fr) 1993-11-10 1995-05-18 University Of British Columbia Procede de traitement utilisant un herpesvirus-1 recombine, sa technique de preparation et composition le contenant
WO1995013392A1 (fr) 1993-11-09 1995-05-18 Medical College Of Ohio Lignees cellulaires stables aptes a exprimer le gene de replication du virus adeno-associe
US5585479A (en) * 1992-07-24 1996-12-17 The United States Of America As Represented By The Secretary Of The Navy Antisense oligonucleotides directed against human ELAM-I RNA

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5212082A (en) * 1991-03-13 1993-05-18 New York University Genetically modified tyrosine hydroxylase and uses thereof
US5587308A (en) * 1992-06-02 1996-12-24 The United States Of America As Represented By The Department Of Health & Human Services Modified adeno-associated virus vector capable of expression from a novel promoter
WO1995028493A1 (fr) * 1994-04-13 1995-10-26 The Rockefeller University Transmission par virus adenoassocie d'adn a des cellules du systeme nerveux

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4797368A (en) * 1985-03-15 1989-01-10 The United States Of America As Represented By The Department Of Health And Human Services Adeno-associated virus as eukaryotic expression vector
US5139941A (en) * 1985-10-31 1992-08-18 University Of Florida Research Foundation, Inc. AAV transduction vectors
US5173414A (en) * 1990-10-30 1992-12-22 Applied Immune Sciences, Inc. Production of recombinant adeno-associated virus vectors
US5252479A (en) * 1991-11-08 1993-10-12 Research Corporation Technologies, Inc. Safe vector for gene therapy
US5585479A (en) * 1992-07-24 1996-12-17 The United States Of America As Represented By The Secretary Of The Navy Antisense oligonucleotides directed against human ELAM-I RNA
WO1994013788A1 (fr) 1992-12-04 1994-06-23 University Of Pittsburgh Systeme porteur viral de recombinaison
WO1995013365A1 (fr) 1993-11-09 1995-05-18 Targeted Genetics Corporation Production de titres eleves de vecteurs d'aav recombinants
WO1995013392A1 (fr) 1993-11-09 1995-05-18 Medical College Of Ohio Lignees cellulaires stables aptes a exprimer le gene de replication du virus adeno-associe
WO1995013391A1 (fr) 1993-11-10 1995-05-18 University Of British Columbia Procede de traitement utilisant un herpesvirus-1 recombine, sa technique de preparation et composition le contenant

Non-Patent Citations (59)

* Cited by examiner, † Cited by third party
Title
Akli et al (1993) Nature Genetics 3:224-228.
Allen et al. (1987) Proc. Natl. Acad. Sci. USA 84:2532-6.
Andersen et al. (1992) Human Gene Therapy 3:487-99.
Bajoccchi et al (1993) 3:229-234.
Breakefield et al. (1991) The New Biologist 3:203-18.
Chatterjee et al., Methods, 5:51-59 (1993). *
Chatterjee, et al., Science, 258:1485-88 (1992).
Chen et al., J. Cellular Biochemistry, 45:252-257 (1991). *
Davidson et al (1993) Nature Genetics 3:219-223.
de Fiebre et al. (1992) Soc. Neurosci. Abst. 18:1-2 (Abstract 331.2).
de Fiebre et al. (1993) Neurochem. Res. 18:1089-94.
de Fiebre et al. (1994) Neurochem. Res. 19:643-8.
During et al., Gene Therapy, vol. 5, pp. 820-827, 1998. *
During et. al. (1994) Abstr. Soc. Neurosci. 20, 1465 (Abs. 602.10).
During et. al. (1994) Science 266:1399-403.
Federoff et al. (1992) Proc. Natl. Acad. Sci. USA 89:1636-40.
Fisher et al., Neuron, 6:371-380 (1991). *
Flothe, et al., J. Biol. Chem., 268:3781-90 (1993).
Flotte, et al., Am. J. Respir. Cell. Mol. Biol., 7:349-56 (1992).
Flotte, et al., Proc. Nat. Acad. Sci. (USA), 90:10613-17 (1993).
Gura, Science, vol. 270, pp. 575-577, Oct. 1995. *
Ho et al. (1988) Virology 167:279-83.
Horellu et al. (1994) Neuroreport 6:49-53.
Isacson, O. (1995) Science 269:856-7.
Jiao et al., Nature, 362:450-453 (1993). *
Kaplitt et al. (1991) Mol. Cellular Neurosciences 2:320-30.
Kaplitt et al. (1993) In: Current Top. Neuroendocrinol. vol. 11, pp. 169-191.
Kaplitt et al. (1994) Nature Genetics 8:148-53.
Klein et al., Neuroscience, vol. 90, No. 3, pp. 815-821, May 1999. *
Kremer et al. (1995) British Med. Bulletin 51:31-44.
Le Gal La Salle et al., "An adenovirus vector for gene transfer into neurons and glia in the brain", Science 259: 988-90 (1993).
Le Gall La Salle, G. Editorial, "Adventures with adenovirus", Nature Genetics 3:1-2 (1993).
Lewis, R. (1995) Genetic Eng. News 15, No. 7: cover,17,25.
Mandel et al., Experimental Neurology, vol. 155, pp. 59-64, 1999. *
Mandel et al., Journal of Neuroscience, vol. 18, No. 11, pp. 4271-4284, Jun. 1, 1998. *
McLaughlin et al. (1988) J. Virology 62:1963-73.
Muro-Cacho, et al., J. Immunother., 11:231-237 (1992).
Muzycka, N. (1994) J. Clin. Invest. 94:1351.
Muzyczka, N., Current Topics in Microbiology and Immunology, 158:97-129 (1992). *
Neve, "Adenovirus vectors enter the brain", TIBS, 16:251-253 (1993).
Ohi et al. (1990) Gene 89:279-82.
Orkin et al., NIH Gene Therapy Meeting Report, Dec. 7, 1995. *
Palella et al. (1988) Mol. Cell. Biol. 457-60.
Palella et al. (1989) Gene 80:137-44.
Roessler et al. (1994) Neurosci. Lett. 167:5-10.
Samulski et al. (1991) EMBO J. 10:3941-50.
Samulski et al., J. Virol., 61:3096-101 (1987).
Samulski et al., J. Virol., 63:3822-28 (1989).
Samulski, Curr. Op. Gen. Devel., 3:74-80 (1993).
Spaete et al. (1982) Cell 30:295-304.
Srivastava, A. (1994) Blood Cells 20:531-8.
Szczypka et al., Neuron, vol. 22, pp. 167-178, Jan. 1999. *
Tenenbaum et al., Meeting on Gene Transfer into Neurons, Abstract, Aug. 16-18, 1993. *
Walsh, et al., Proc. Nat. Acad. Sci. (USA), 89:7257-61 (1992).
Wolff (1993) Curr. Opin. Neurobiology 3:743-748.
Wolff et al., PNAS USA, 86:9011-9014 (1989). *
Wu et al. (1994) Mol. Brain Res. 24:27-33.
Wu et al., Society for Neuroscience Abstracts, vol. 19, No. 1-3, pp. 391, Abstract # 160.14, Nov. 7, 1993. *
Xiao et al., Advanced Drug Delivery Reviews, 12:201-215 (1993). *

Cited By (464)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6503888B1 (en) * 1994-04-13 2003-01-07 The Rockefeller University AAV-mediated delivery of DNA to cells of the nervous system
US20100310601A1 (en) * 1994-06-06 2010-12-09 Nationwide Children's Hospital Inc. Adeno-Associated Virus Materials and Methods
US20060204519A1 (en) * 1994-06-06 2006-09-14 Children's Hospital Inc. Adeno-associated virus materials and methods
US7070998B2 (en) * 1994-06-06 2006-07-04 Children's Hospital, Inc. Adeno-associated virus materials and methods
US7662627B2 (en) * 1994-06-06 2010-02-16 Nationwide Children's Hospital, Inc. Adeno-associated virus materials and methods
US20050169892A1 (en) * 1994-06-06 2005-08-04 Children's Hospital, Inc. Adeno-associated virus materials and methods
US20030147912A1 (en) * 1994-06-06 2003-08-07 Johnson Philip R. Adeno-associated virus materials and methods
US20030082145A1 (en) * 1994-06-06 2003-05-01 Johnson Philip R. Adeno-associated virus materials and methods
US20040220128A1 (en) * 1995-10-26 2004-11-04 Sirna Therapeutics, Inc. Nucleic acid based modulation of female reproductive diseases and conditions
US20040142895A1 (en) * 1995-10-26 2004-07-22 Sirna Therapeutics, Inc. Nucleic acid-based modulation of gene expression in the vascular endothelial growth factor pathway
US20030223971A1 (en) * 1996-03-06 2003-12-04 Kurtzman Gary J. Gene therapy for the treatment of solid tumors using recombinant adeno-associated virus vectors
US8507267B2 (en) 1996-09-11 2013-08-13 U.S. Dept. of Health and Human Services, National Institutes of Health AAV4 vector and uses thereof
US20040086490A1 (en) * 1996-09-11 2004-05-06 Sumesh Kaushal AAV4 vector and uses thereof
US7718424B2 (en) 1996-09-11 2010-05-18 The United States Of America As Represented By The Department Of Health And Human Services AAV4 vector and uses thereof
US8846389B2 (en) 1996-09-11 2014-09-30 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services AAV4 vector and uses thereof
US20030036511A1 (en) * 1996-12-13 2003-02-20 Chiron Corporation Analysis and separation of platelet-derived growth factor proteins
US6436708B1 (en) * 1997-04-17 2002-08-20 Paola Leone Delivery system for gene therapy to the brain
US8110556B2 (en) * 1997-09-16 2012-02-07 University Of Medicine And Dentistry Of New Jersey Method of expressing human lysosomal protein in brain cells
US20080051358A1 (en) * 1997-09-16 2008-02-28 New Jersey University Of Med. And Dentistry Of New Jersey Novel human lysosomal protein and methods of its use
US6953575B2 (en) 1998-05-27 2005-10-11 Avigen, Inc. Methods of treating central nervous system disorders using viral vectors
US7534613B2 (en) 1998-05-27 2009-05-19 Genzyme Corporation Methods of treating parkinson's disease using viral vectors
US8309355B2 (en) 1998-05-27 2012-11-13 Genzyme Corporation Methods of treating Parkinson's disease using viral vectors
US20100104537A1 (en) * 1998-05-27 2010-04-29 Regents Of The University Of California Methods of treating Parkinson's disease using viral vectors
US20050180955A1 (en) * 1998-05-27 2005-08-18 Regents Of The University Of California Methods of treating parkinson's disease using viral vectors
US9492415B2 (en) 1998-05-27 2016-11-15 Genzyme Corporation Methods of treating Parkinson's disease using viral vectors
US20050255089A1 (en) * 1998-05-28 2005-11-17 Chiorini John A AAV5 nucleic acids
US7479554B2 (en) 1998-05-28 2009-01-20 The United States Of America As Represented By The Department Of Health And Human Services AAV5 nucleic acids
US20030203870A1 (en) * 2000-02-11 2003-10-30 Ribozyme Pharmaceuticals, Inc. Method and reagent for the inhibition of NOGO and NOGO receptor genes
US20050261212A1 (en) * 2000-02-11 2005-11-24 Mcswiggen James A RNA interference mediated inhibition of NOGO and NOGO receptor gene expression using short interfering RNA
US20070026394A1 (en) * 2000-02-11 2007-02-01 Lawrence Blatt Modulation of gene expression associated with inflammation proliferation and neurite outgrowth using nucleic acid based technologies
US20040009510A1 (en) * 2000-03-06 2004-01-15 Scott Seiwert Allosteric nucleic acid sensor molecules
US20030065155A1 (en) * 2000-03-06 2003-04-03 Nassim Usman Nucleic acid sensor molecules
US6855314B1 (en) * 2000-03-22 2005-02-15 The United States Of America As Represented By The Department Of Health And Human Services AAV5 vector for transducing brain cells and lung cells
US7645446B2 (en) * 2000-05-23 2010-01-12 Neurologix, Inc. Glutamic acid decarboxylase (GAD) based delivery system
US20020091094A1 (en) * 2000-05-23 2002-07-11 During Matthew J. Glutamic acid decarboxylase (GAD) based delivery system
US6780409B2 (en) * 2000-05-23 2004-08-24 Thomas Jefferson University Glutamic acid decarboxylase (GAD) based delivery system
US20060099179A1 (en) * 2000-05-23 2006-05-11 Neurologix, Inc. Glutamic acid decarboxylase (GAD) based delivery system
US20050209179A1 (en) * 2000-08-30 2005-09-22 Sirna Therapeutics, Inc. RNA interference mediated treatment of Alzheimer's disease using short interfering nucleic acid (siNA)
US20080032942A1 (en) * 2000-08-30 2008-02-07 Mcswiggen James RNA interference mediated treatment of Alzheimer's disease using short interfering nucleic acid (siNA)
US20020172664A1 (en) * 2001-03-14 2002-11-21 Keiya Ozawa Methods of treating Parkinson's disease using recombinant adeno-associated virus virions
US7588757B2 (en) 2001-03-14 2009-09-15 Genzyme Corporation Methods of treating Parkinson's disease using recombinant adeno-associated virus virions
US20030191077A1 (en) * 2001-04-05 2003-10-09 Kathy Fosnaugh Method and reagent for the treatment of asthma and allergic conditions
US20050080031A1 (en) * 2001-05-18 2005-04-14 Sirna Therapeutics, Inc. Nucleic acid treatment of diseases or conditions related to levels of Ras, HER2 and HIV
US20050164967A1 (en) * 2001-05-18 2005-07-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of platelet-derived endothelial cell growth factor (ECGF1) gene expression using short interfering nucleic acid (siNA)
US20070160980A1 (en) * 2001-05-18 2007-07-12 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA)
US20050032733A1 (en) * 2001-05-18 2005-02-10 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (SiNA)
US20050282188A1 (en) * 2001-05-18 2005-12-22 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA)
US20070270579A1 (en) * 2001-05-18 2007-11-22 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA)
US9994853B2 (en) 2001-05-18 2018-06-12 Sirna Therapeutics, Inc. Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference
US20050267058A1 (en) * 2001-05-18 2005-12-01 Sirna Therapeutics, Inc. RNA interference mediated inhibition of placental growth factor gene expression using short interfering nucleic acid (sINA)
US20080161256A1 (en) * 2001-05-18 2008-07-03 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA)
US20060241075A1 (en) * 2001-05-18 2006-10-26 Sirna Therapeutics, Inc. RNA interference mediated inhibition of desmoglein gene expression using short interfering nucleic acid (siNA)
US20060217332A1 (en) * 2001-05-18 2006-09-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20050079610A1 (en) * 2001-05-18 2005-04-14 Sirna Therapeutics, Inc. RNA interference mediated inhibition of Fos gene expression using short interfering nucleic acid (siNA)
US20050287128A1 (en) * 2001-05-18 2005-12-29 Sirna Therapeutics, Inc. RNA interference mediated inhibition of TGF-beta and TGF-beta receptor gene expression using short interfering nucleic acid (siNA)
US20060216747A1 (en) * 2001-05-18 2006-09-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of checkpoint kinase-1 (CHK-1) gene expression using short interfering nucleic acid (siNA)
US20050119211A1 (en) * 2001-05-18 2005-06-02 Sirna Therapeutics, Inc. RNA mediated inhibition connexin gene expression using short interfering nucleic acid (siNA)
US20050119212A1 (en) * 2001-05-18 2005-06-02 Sirna Therapeutics, Inc. RNA interference mediated inhibition of FAS and FASL gene expression using short interfering nucleic acid (siNA)
US20050124567A1 (en) * 2001-05-18 2005-06-09 Sirna Therapeutics, Inc. RNA interference mediated inhibition of TRPM7 gene expression using short interfering nucleic acid (siNA)
US20050124568A1 (en) * 2001-05-18 2005-06-09 Sirna Therapeutics, Inc. RNA interference mediated inhibition of acetyl-CoA-carboxylase gene expression using short interfering nucleic acid (siNA)
US20050124566A1 (en) * 2001-05-18 2005-06-09 Sirna Therapeutics, Inc. RNA interference mediated inhibition of myostatin gene expression using short interfering nucleic acid (siNA)
US20050130181A1 (en) * 2001-05-18 2005-06-16 Sirna Therapeutics, Inc. RNA interference mediated inhibition of wingless gene expression using short interfering nucleic acid (siNA)
US20060211642A1 (en) * 2001-05-18 2006-09-21 Sirna Therapeutics, Inc. RNA inteference mediated inhibition of hepatitis C virus (HVC) gene expression using short interfering nucleic acid (siNA)
US20050137155A1 (en) * 2001-05-18 2005-06-23 Sirna Therapeutics, Inc. RNA interference mediated treatment of Parkinson disease using short interfering nucleic acid (siNA)
US20050136436A1 (en) * 2001-05-18 2005-06-23 Sirna Therapeutics, Inc. RNA interference mediated inhibition of G72 and D-amino acid oxidase (DAAO) gene expression using short interfering nucleic acid (siNA)
US20080188430A1 (en) * 2001-05-18 2008-08-07 Sirna Therapeutics, Inc. RNA interference mediated inhibition of hypoxia inducible factor 1 (HIF1) gene expression using short interfering nucleic acid (siNA)
US20050143333A1 (en) * 2001-05-18 2005-06-30 Sirna Therapeutics, Inc. RNA interference mediated inhibition of interleukin and interleukin receptor gene expression using short interfering nucleic acid (SINA)
US7517864B2 (en) 2001-05-18 2009-04-14 Sirna Therapeutics, Inc. RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20050153914A1 (en) * 2001-05-18 2005-07-14 Sirna Therapeutics, Inc. RNA interference mediated inhibition of MDR P-glycoprotein gene expression using short interfering nucleic acid (siNA)
US20050153915A1 (en) * 2001-05-18 2005-07-14 Sirna Therapeutics, Inc. RNA interference mediated inhibition of early growth response gene expression using short interfering nucleic acid (siNA)
US20050159382A1 (en) * 2001-05-18 2005-07-21 Sirna Therapeutics, Inc. RNA interference mediated inhibition of polycomb group protein EZH2 gene expression using short interfering nucleic acid (siNA)
US20050159379A1 (en) * 2001-05-18 2005-07-21 Sirna Therapeutics, Inc RNA interference mediated inhibition of gastric inhibitory polypeptide (GIP) and gastric inhibitory polypeptide receptor (GIPR) gene expression using short interfering nucleic acid (siNA)
US20060142225A1 (en) * 2001-05-18 2006-06-29 Sirna Therapeutics, Inc. RNA interference mediated inhibition of cyclin dependent kinase-2 (CDK2) gene expression using short interfering nucleic acid (siNA)
US20050159380A1 (en) * 2001-05-18 2005-07-21 Sirna Therapeutics, Inc. RNA interference mediated inhibition of angiopoietin gene expression using short interfering nucleic acid (siNA)
US20050164224A1 (en) * 2001-05-18 2005-07-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of cyclin D1 gene expression using short interfering nucleic acid (siNA)
US20050256068A1 (en) * 2001-05-18 2005-11-17 Sirna Therapeutics, Inc. RNA interference mediated inhibition of stearoyl-CoA desaturase (SCD) gene expression using short interfering nucleic acid (siNA)
US20050164968A1 (en) * 2001-05-18 2005-07-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of ADAM33 gene expression using short interfering nucleic acid (siNA)
US20050164966A1 (en) * 2001-05-18 2005-07-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of type 1 insulin-like growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20060142226A1 (en) * 2001-05-18 2006-06-29 Sirna Therapeutics, Inc. RNA interference mediated inhibition of cholesteryl ester transfer protein (CETP) gene expression using short interfering nucleic acid (siNA)
US20050233997A1 (en) * 2001-05-18 2005-10-20 Sirna Therapeutics, Inc. RNA interference mediated inhibition of matrix metalloproteinase 13 (MMP13) gene expression using short interfering nucleic acid (siNA)
US20050176665A1 (en) * 2001-05-18 2005-08-11 Sirna Therapeutics, Inc. RNA interference mediated inhibition of hairless (HR) gene expression using short interfering nucleic acid (siNA)
US20050176666A1 (en) * 2001-05-18 2005-08-11 Sirna Therapeutics, Inc. RNA interference mediated inhibition of GPRA and AAA1 gene expression using short interfering nucleic acid (siNA)
US20050176664A1 (en) * 2001-05-18 2005-08-11 Sirna Therapeutics, Inc. RNA interference mediated inhibition of cholinergic muscarinic receptor (CHRM3) gene expression using short interfering nucleic acid (siNA)
US20050182006A1 (en) * 2001-05-18 2005-08-18 Sirna Therapeutics, Inc RNA interference mediated inhibition of protein kinase C alpha (PKC-alpha) gene expression using short interfering nucleic acid (siNA)
US20050182009A1 (en) * 2001-05-18 2005-08-18 Sirna Therapeutics, Inc. RNA interference mediated inhibition of NF-Kappa B / REL-A gene expression using short interfering nucleic acid (siNA)
US20050288242A1 (en) * 2001-05-18 2005-12-29 Sirna Therapeutics, Inc. RNA interference mediated inhibition of RAS gene expression using short interfering nucleic acid (siNA)
US20050182007A1 (en) * 2001-05-18 2005-08-18 Sirna Therapeutics, Inc. RNA interference mediated inhibition of interleukin and interleukin receptor gene expression using short interfering nucleic acid (SINA)
US20050187174A1 (en) * 2001-05-18 2005-08-25 Sirna Therapeutics, Inc. RNA interference mediated inhibition of intercellular adhesion molecule (ICAM) gene expression using short interfering nucleic acid (siNA)
US20050233344A1 (en) * 2001-05-18 2005-10-20 Sirna Therapeutics, Inc. RNA interference mediated inhibition of platelet derived growth factor (PDGF) and platelet derived growth factor receptor (PDGFR) gene expression using short interfering nucleic acid (siNA)
US20050196767A1 (en) * 2001-05-18 2005-09-08 Sirna Therapeutics, Inc. RNA interference mediated inhibition of GRB2 associated binding protein (GAB2) gene expression using short interfering nucleic acis (siNA)
US20050196765A1 (en) * 2001-05-18 2005-09-08 Sirna Therapeutics, Inc. RNA interference mediated inhibition of checkpoint Kinase-1 (CHK-1) gene expression using short interfering nucleic acid (siNA)
US20050203040A1 (en) * 2001-05-18 2005-09-15 Sirna Therapeutics, Inc. RNA interference mediated inhibition of vascular cell adhesion molecule (VCAM) gene expression using short interfering nucleic acid (siNA)
US20050209180A1 (en) * 2001-05-18 2005-09-22 Sirna Therapeutics, Inc. RNA interference mediated inhibition of hepatitis C virus (HCV) expression using short interfering nucleic acid (siNA)
US20060025361A1 (en) * 2001-05-18 2006-02-02 Sirna Therapeutics, Inc. RNA interference mediated inhibition of protein tyrosine phosphatase-1B (PTP-1B) gene expression using short interfering nucleic acid (siNA)
US20050227935A1 (en) * 2001-05-18 2005-10-13 Sirna Therapeutics, Inc. RNA interference mediated inhibition of TNF and TNF receptor gene expression using short interfering nucleic acid (siNA)
US20050222066A1 (en) * 2001-05-18 2005-10-06 Sirna Therapeutics, Inc. RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20060019913A1 (en) * 2001-05-18 2006-01-26 Sirna Therapeutics, Inc. RNA interference mediated inhibtion of protein tyrosine phosphatase-1B (PTP-1B) gene expression using short interfering nucleic acid (siNA)
US20030105051A1 (en) * 2001-05-29 2003-06-05 Mcswiggen James Nucleic acid treatment of diseases or conditions related to levels of HER2
US20030153521A1 (en) * 2001-05-29 2003-08-14 Mcswiggen James Nucleic acid treatment of diseases or conditions related to levels of Ras
US20030140362A1 (en) * 2001-06-08 2003-07-24 Dennis Macejak In vivo models for screening inhibitors of hepatitis B virus
WO2003015713A3 (fr) * 2001-08-20 2003-11-27 Maiken Nedergaard Traitement de tumeurs gliales avec des antagonistes du glutamate
US20030050224A1 (en) * 2001-08-20 2003-03-13 Maiken Nedergaard Treatment of glial tumors with glutamate antagonists
US7250394B2 (en) 2001-08-20 2007-07-31 Maiken Nedergaard Treatment of glial tumors with glutamate antagonists
WO2003015713A2 (fr) * 2001-08-20 2003-02-27 Maiken Nedergaard Traitement de tumeurs gliales avec des antagonistes du glutamate
AU2002329799B2 (en) * 2001-08-20 2007-03-15 Maiken Nedergaard Treatment of glial tumors with glutamate antagonists
US20070135413A1 (en) * 2001-08-20 2007-06-14 Maiken Nedergaard Treatment of glial tumors with glutamate antagonists
US20050233990A1 (en) * 2001-08-29 2005-10-20 Yong-Serk Park Anti-cancer agents comprising disintegrin genes and the treating methods
US20030061184A1 (en) * 2001-09-27 2003-03-27 Csem Centre Suisse D'electronique Et De Microtechnique S.A. Method and a system for calculating the values of the neurons of a neural network
US20050070493A1 (en) * 2001-10-30 2005-03-31 Fawell Stephen Eric Methods and compositions for treating Parkinson's disease
US20040198682A1 (en) * 2001-11-30 2004-10-07 Mcswiggen James RNA interference mediated inhibition of placental growth factor gene expression using short interfering nucleic acid (siNA)
US20070203333A1 (en) * 2001-11-30 2007-08-30 Mcswiggen James RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20050054596A1 (en) * 2001-11-30 2005-03-10 Mcswiggen James RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20050075304A1 (en) * 2001-11-30 2005-04-07 Mcswiggen James RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
EP1463530A4 (fr) * 2001-12-19 2006-09-06 Lijun Wang Administration de gdnf induite par le virus adeno-associe dans des muscles du squelette
WO2003053476A1 (fr) * 2001-12-19 2003-07-03 Lijun Wang Administration de gdnf induite par le virus adeno-associe dans des muscles du squelette
US20030161814A1 (en) * 2001-12-19 2003-08-28 Lijun Wang Adeno-associated virus-mediated delivery of GDNF to skeletal muscles
EP1463530A1 (fr) * 2001-12-19 2004-10-06 Lijun Wang Administration de gdnf induite par le virus adeno-associe dans des muscles du squelette
US20060292123A1 (en) * 2001-12-19 2006-12-28 Genzyme Corporation Adeno-associated virus-mediated delivery of GDNF to skeletal muscles
US7112321B2 (en) 2001-12-19 2006-09-26 Genzyme Corporation Adeno-associated virus-mediated delivery of GDNF to skeletal muscles
US20050042632A1 (en) * 2002-02-13 2005-02-24 Sirna Therapeutics, Inc. Antibodies having specificity for nucleic acids
US9738899B2 (en) 2002-02-20 2017-08-22 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20050159376A1 (en) * 2002-02-20 2005-07-21 Slrna Therapeutics, Inc. RNA interference mediated inhibition 5-alpha reductase and androgen receptor gene expression using short interfering nucleic acid (siNA)
US20050137153A1 (en) * 2002-02-20 2005-06-23 Sirna Therapeutics, Inc. RNA interference mediated inhibition of alpha-1 antitrypsin (AAT) gene expression using short interfering nucleic acid (siNA)
US20050233996A1 (en) * 2002-02-20 2005-10-20 Sirna Therapeutics, Inc. RNA interference mediated inhibition of hairless (HR) gene expression using short interfering nucleic acid (siNA)
US20050096284A1 (en) * 2002-02-20 2005-05-05 Sirna Therapeutics, Inc. RNA interference mediated treatment of polyglutamine (polyQ) repeat expansion diseases using short interfering nucleic acid (siNA)
US10662428B2 (en) 2002-02-20 2020-05-26 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20060217335A1 (en) * 2002-02-20 2006-09-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20080039414A1 (en) * 2002-02-20 2008-02-14 Sima Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20060217336A1 (en) * 2002-02-20 2006-09-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20060217337A1 (en) * 2002-02-20 2006-09-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20060217334A1 (en) * 2002-02-20 2006-09-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20050191638A1 (en) * 2002-02-20 2005-09-01 Sirna Therapeutics, Inc. RNA interference mediated treatment of polyglutamine (polyQ) repeat expansion diseases using short interfering nucleic acid (siNA)
US20050222064A1 (en) * 2002-02-20 2005-10-06 Sirna Therapeutics, Inc. Polycationic compositions for cellular delivery of polynucleotides
US20060247428A1 (en) * 2002-02-20 2006-11-02 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US10351852B2 (en) 2002-02-20 2019-07-16 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20060275903A1 (en) * 2002-02-20 2006-12-07 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20060281175A1 (en) * 2002-02-20 2006-12-14 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20060287266A1 (en) * 2002-02-20 2006-12-21 Sirna Therapeutics, Inc. RNA interference mediated ihibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20050148530A1 (en) * 2002-02-20 2005-07-07 Sirna Therapeutics, Inc. RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20040192626A1 (en) * 2002-02-20 2004-09-30 Mcswiggen James RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20060292691A1 (en) * 2002-02-20 2006-12-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20060293272A1 (en) * 2002-02-20 2006-12-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20070004667A1 (en) * 2002-02-20 2007-01-04 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20050054598A1 (en) * 2002-02-20 2005-03-10 Sirna Therapeutics, Inc. RNA interference mediated inhibition hairless (HR) gene expression using short interfering nucleic acid (siNA)
US7176304B2 (en) 2002-02-20 2007-02-13 Mcswiggen James RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20030190635A1 (en) * 2002-02-20 2003-10-09 Mcswiggen James A. RNA interference mediated treatment of Alzheimer's disease using short interfering RNA
US20040209831A1 (en) * 2002-02-20 2004-10-21 Mcswiggen James RNA interference mediated inhibition of hepatitis C virus (HCV) gene expression using short interfering nucleic acid (siNA)
US10000754B2 (en) 2002-02-20 2018-06-19 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US8846894B2 (en) 2002-02-20 2014-09-30 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US7989612B2 (en) 2002-02-20 2011-08-02 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US9957517B2 (en) 2002-02-20 2018-05-01 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20050014172A1 (en) * 2002-02-20 2005-01-20 Ivan Richards RNA interference mediated inhibition of muscarinic cholinergic receptor gene expression using short interfering nucleic acid (siNA)
US20070167393A1 (en) * 2002-02-20 2007-07-19 Sirna Therapeutics, Inc. RNA INTERFERENCE MEDIATED INHIBITION OF GENE EXPRESSION USING CHEMICALLY MODIFIED SHORT INTERFERING NUCLEIC ACID (siNA)
US20040219671A1 (en) * 2002-02-20 2004-11-04 Sirna Therapeutics, Inc. RNA interference mediated treatment of parkinson disease using short interfering nucleic acid (siNA)
US8273866B2 (en) 2002-02-20 2012-09-25 Merck Sharp & Dohme Corp. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (SINA)
US9771588B2 (en) 2002-02-20 2017-09-26 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20050171039A1 (en) * 2002-02-20 2005-08-04 Sirna Therapeutics, Inc. RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US10889815B2 (en) 2002-02-20 2021-01-12 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US9732344B2 (en) 2002-02-20 2017-08-15 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US9181551B2 (en) 2002-02-20 2015-11-10 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US9657294B2 (en) 2002-02-20 2017-05-23 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US8202979B2 (en) 2002-02-20 2012-06-19 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid
US20060293271A1 (en) * 2002-02-20 2006-12-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20090137500A1 (en) * 2002-02-20 2009-05-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20040018520A1 (en) * 2002-04-22 2004-01-29 James Thompson Trans-splicing enzymatic nucleic acid mediated biopharmaceutical and protein
US20030228284A1 (en) * 2002-04-30 2003-12-11 University Of North Carolina At Chapel Hill Secretion signal vectors
US7071172B2 (en) 2002-04-30 2006-07-04 The University Of North Carolina At Chapel Hill Secretion signal vectors
US20040110266A1 (en) * 2002-05-17 2004-06-10 Chiorini John A. Scalable purification of AAV2, AAV4 or AAV5 using ion-exchange chromatography
US7419817B2 (en) 2002-05-17 2008-09-02 The United States Of America As Represented By The Secretary Department Of Health And Human Services, Nih. Scalable purification of AAV2, AAV4 or AAV5 using ion-exchange chromatography
US20040138163A1 (en) * 2002-05-29 2004-07-15 Mcswiggen James RNA interference mediated inhibition of vascular edothelial growth factor and vascular edothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20040014698A1 (en) * 2002-07-18 2004-01-22 Gonzalo Hortelano Oral administration of therapeutic agent coupled to transporting agent
US20040016013A1 (en) * 2002-07-18 2004-01-22 Gonzalo Hortelano Transgenic animals produced using oral administration of a genetic agent coupled to a transporting agent
US7956176B2 (en) 2002-09-05 2011-06-07 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US7923547B2 (en) 2002-09-05 2011-04-12 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20050143330A1 (en) * 2002-09-30 2005-06-30 Ron Mandel Method for the treatment of Parkinson's Disease
US20050010261A1 (en) * 2002-10-21 2005-01-13 The Cleveland Clinic Foundation Application of stimulus to white matter to induce a desired physiological response
US20090060987A1 (en) * 2002-11-26 2009-03-05 Kaemmerer William F Devices, systems and methods for improving memory and/or cognitive function through brain delivery of sirna
US20040162255A1 (en) * 2002-11-26 2004-08-19 Medtronic, Inc. Treatment of neurodegenerative disease through intracranial delivery of siRNA
US7605249B2 (en) 2002-11-26 2009-10-20 Medtronic, Inc. Treatment of neurodegenerative disease through intracranial delivery of siRNA
US8415319B2 (en) 2002-11-26 2013-04-09 Medtronic, Inc. Devices, systems and methods for improving memory and/or cognitive function through brain delivery of siRNA
US20060178328A1 (en) * 2002-11-26 2006-08-10 Medtronic Inc. Devices, systems and methods for improving memory and/or cognitive function through brain delivery of siRNA
US8618069B2 (en) 2002-11-26 2013-12-31 Medtronic, Inc. Devices, systems and methods for improving memory and/or cognitive function through brain delivery of siRNA
US7829694B2 (en) 2002-11-26 2010-11-09 Medtronic, Inc. Treatment of neurodegenerative disease through intracranial delivery of siRNA
US8058251B2 (en) 2002-11-26 2011-11-15 Kaemmerer William F Devices, systems and methods for improving memory and/or cognitive function through brain delivery of siRNA
US20100063134A1 (en) * 2002-11-26 2010-03-11 Medtronic, Inc. Treatment of neurodegenerative disease through intracranial delivery of sirna
US7618948B2 (en) * 2002-11-26 2009-11-17 Medtronic, Inc. Devices, systems and methods for improving and/or cognitive function through brain delivery of siRNA
US20040220132A1 (en) * 2002-11-26 2004-11-04 Medtronic, Inc. Treatment of neurodegenerative disease through intracranial delivery of siRNA
US8119611B2 (en) 2002-11-26 2012-02-21 Medtronic, Inc. Treatment of neurodegenerative disease through intracranial delivery of SIRNA
US20040231231A1 (en) * 2002-12-20 2004-11-25 Cataldo Dominic A. Use of colloidal clays for sustained release of active ingredients
EP2181704A2 (fr) 2002-12-30 2010-05-05 Angiotech International Ag Liberation de medicaments a partir d'une compostion polymere a gelification rapide
US8957198B2 (en) 2003-02-03 2015-02-17 Medtronic, Inc. Compositions, devices and methods for treatment of Huntington's disease through intracranial delivery of sirna
US7341847B2 (en) 2003-04-02 2008-03-11 Agency For Science, Technology And Research Promoter construct for gene expression in neuronal cells
US20040197313A1 (en) * 2003-04-02 2004-10-07 Institute Of Materials Research And Engineering Promoter construct for gene expression in neuronal cells
US20040258666A1 (en) * 2003-05-01 2004-12-23 Passini Marco A. Gene therapy for neurometabolic disorders
US10913956B2 (en) * 2003-05-01 2021-02-09 Genzyme Corporation Gene therapy for neurometabolic disorders
EP3513814A1 (fr) 2003-05-01 2019-07-24 Genzyme Corporation Thérapie génique pour les troubles neurométaboliques
US20170152524A1 (en) * 2003-05-01 2017-06-01 Genzyme Corporation Gene therapy for neurometabolic disorders
WO2004098648A1 (fr) 2003-05-01 2004-11-18 Genzyme Corporation Therapie genique pour troubles neurometaboliques
US9238800B2 (en) 2003-05-19 2016-01-19 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Avian adenoassociated virus and uses thereof
US8927269B2 (en) 2003-05-19 2015-01-06 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Avian adenoassociated virus and uses thereof
US7186699B2 (en) 2003-06-03 2007-03-06 Cell Genesys, Inc. Method for treating cancer by vector-mediated delivery of one or more anti-angiogenic or pro-apoptotic genes
US20050031593A1 (en) * 2003-06-03 2005-02-10 Thomas Harding Method for treating cancer by vector-mediated delivery of one or more anti-angiogenic or pro-apoptotic genes
US20110059041A1 (en) * 2003-09-12 2011-03-10 Alemseged Truneh Vaccine for treatment and prevention of herpes simplex virus infection
US8541002B2 (en) 2003-09-12 2013-09-24 Agenus Inc. Vaccine for treatment and prevention of herpes simplex virus infection
EP2210617A1 (fr) 2003-10-20 2010-07-28 NsGene A/S Cellules mammifères sécrétant de la neurturine et leur usage thérapeutique
US20060239966A1 (en) * 2003-10-20 2006-10-26 Tornoee Jens In vivo gene therapy of parkinson's disease
US7732591B2 (en) 2003-11-25 2010-06-08 Medtronic, Inc. Compositions, devices and methods for treatment of huntington's disease through intracranial delivery of sirna
US20070167389A1 (en) * 2003-11-25 2007-07-19 Kaemmerer William F Compositions, devices and methods for treatment of huntington's disease through intracranial delivery of sirna
US8137960B2 (en) 2003-12-04 2012-03-20 The United States Of America As Represented By The Department Of Health And Human Services Bovine adeno-associated viral (BAAV) vector and uses thereof
US9193769B2 (en) 2003-12-04 2015-11-24 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Bovine adeno-associated viral (BAAV) vector and uses thereof
US8685722B2 (en) 2003-12-04 2014-04-01 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Bovine adeno-associated viral (BAAV) vector and uses thereof
US20070072282A1 (en) * 2003-12-04 2007-03-29 Chiorini John A Bovine adeno-associated viral (baav) vector and uses thereof
US20050208032A1 (en) * 2004-01-16 2005-09-22 Gonzalo Hortelano Oral administration of therapeutic agent coupled to transporting agent
US20110213328A1 (en) * 2004-03-18 2011-09-01 Medtronic, Inc. Methods and Systems for Treatment of Neurological Diseases of the Central Nervous System
US20060171926A1 (en) * 2004-04-30 2006-08-03 Passini Marco A Gene therapy for neurometabolic disorders
US7811814B2 (en) 2004-05-18 2010-10-12 Children's Memorial Hospital Tetracycline-regulated adeno-associated viral (AAV) vectors for gene delivery to the nervous system
US7456015B2 (en) 2004-05-18 2008-11-25 Children's Memorial Hospital Tetracycline-regulated adeno-associated viral (AAV) vectors for gene delivery to the nervous system
US20090149409A1 (en) * 2004-05-18 2009-06-11 Children's Memorial Hospital Tetracycline-Regulated Adeno-Associated Viral (AAV) Vectors for Gene Delivery to the Nervous System
US20070148132A1 (en) * 2004-05-18 2007-06-28 Bohn Martha C Tetracycline-regulated adeno-associated viral (AAV) vectors for gene delivery to the nervous system
US10508277B2 (en) 2004-05-24 2019-12-17 Sirna Therapeutics, Inc. Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference
US20050281786A1 (en) * 2004-06-18 2005-12-22 David Poulsen AAV mediated gene delivery to cochlear cells
US20080188431A1 (en) * 2004-09-08 2008-08-07 Chiorini John A Transcytosis of Adeno-Associated Viruses
US20060217330A1 (en) * 2004-12-09 2006-09-28 Gunther Hartmann Compositions and methods for inducing an immune response in a mammal and methods of avoiding an immune response to oligonucleotide agents such as short interfering RNAs
US8003619B2 (en) 2004-12-09 2011-08-23 Alnylam Pharmaceuticals, Inc. Method of stimulating an immune response and inhibiting expression of a gene using an oligonucleotide
EP2360249A1 (fr) 2005-03-31 2011-08-24 Calando Pharmaceuticals, Inc. Inhibiteurs de la sous-unite 2 de la ribonucleotide reductase et utilisations associees
US20060253068A1 (en) * 2005-04-20 2006-11-09 Van Bilsen Paul Use of biocompatible in-situ matrices for delivery of therapeutic cells to the heart
US20100129405A1 (en) * 2005-04-29 2010-05-27 Michael Schmidt Isolation, cloning and characterization of new adeno-associated virus (aav) serotypes
US8283151B2 (en) 2005-04-29 2012-10-09 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Isolation, cloning and characterization of new adeno-associated virus (AAV) serotypes
US10744210B2 (en) 2005-05-02 2020-08-18 Genzyme Corporation Gene therapy for spinal cord disorders
US11957765B2 (en) 2005-05-02 2024-04-16 Genzyme Corporation Gene therapy for neurometabolic disorders
US10632213B2 (en) 2005-05-02 2020-04-28 Genzyme Corporation Gene therapy for neurometabolic disorders
EP2420256A1 (fr) 2005-05-02 2012-02-22 Genzyme Corporation Thérapie génique pour les troubles neurométaboliques
EP3058959A1 (fr) 2005-05-02 2016-08-24 Genzyme Corporation Thérapie génique pour les troubles neurométaboliques
US20090069261A1 (en) * 2005-05-02 2009-03-12 Genzyme Corporation Gene therapy for spinal cord disorders
EP3520823A1 (fr) 2005-05-02 2019-08-07 Genzyme Corporation Thérapie génique pour troubles neurométaboliques
US8258112B2 (en) 2005-05-06 2012-09-04 Medtronic, Inc Methods and sequences to suppress primate huntington gene Expression
US7902352B2 (en) 2005-05-06 2011-03-08 Medtronic, Inc. Isolated nucleic acid duplex for reducing huntington gene expression
US20100008981A1 (en) * 2005-05-06 2010-01-14 Medtronic, Inc. Methods and sequences to suppress primate huntington gene expression
US20100325746A9 (en) * 2005-05-06 2010-12-23 Kaemmerer William F Methods and sequences to suppress primate huntington gene expression in vivo
US20070261126A1 (en) * 2005-05-06 2007-11-08 Kaemmerer William F Methods and sequences to suppress primate huntington gene expression in vivo
US20100120900A1 (en) * 2005-06-28 2010-05-13 Medtronic, Inc. Methods And Sequences To Preferentially Suppress Expression of Mutated Huntingtin
US9133517B2 (en) 2005-06-28 2015-09-15 Medtronics, Inc. Methods and sequences to preferentially suppress expression of mutated huntingtin
WO2007008486A3 (fr) * 2005-07-07 2007-06-07 Genzyme Corp Vecteurs de aav codant pour la superoxyde dismutase
JP2009501009A (ja) * 2005-07-07 2009-01-15 ジェンザイム・コーポレーション スーパーオキシドジスムターゼをコードするａａｖベクター
US20080181872A1 (en) * 2005-07-07 2008-07-31 Mohammad Doroudchi Aav vectors encoding superoxide dismutase
US9829492B2 (en) 2005-07-22 2017-11-28 The Board Of Trustees Of The Leland Stanford Junior University Implantable prosthetic device comprising a cell expressing a channelrhodopsin
US10422803B2 (en) 2005-07-22 2019-09-24 The Board Of Trustees Of The Leland Stanford Junior University Light-activated cation channel and uses thereof
US10451608B2 (en) 2005-07-22 2019-10-22 The Board Of Trustees Of The Leland Stanford Junior University Cell line, system and method for optical-based screening of ion-channel modulators
US10627410B2 (en) 2005-07-22 2020-04-21 The Board Of Trustees Of The Leland Stanford Junior University Light-activated cation channel and uses thereof
US10046174B2 (en) 2005-07-22 2018-08-14 The Board Of Trustees Of The Leland Stanford Junior University System for electrically stimulating target neuronal cells of a living animal in vivo
US10569099B2 (en) 2005-07-22 2020-02-25 The Board Of Trustees Of The Leland Stanford Junior University System for optical stimulation of target cells
US20150165227A1 (en) * 2005-07-22 2015-06-18 The Board Of Trustees Of The Leland Stanford Junior University Light-Activated Cation Channel and Uses Thereof
US10094840B2 (en) * 2005-07-22 2018-10-09 The Board Of Trustees Of The Leland Stanford Junior University Light-activated cation channel and uses thereof
US10052497B2 (en) 2005-07-22 2018-08-21 The Board Of Trustees Of The Leland Stanford Junior University System for optical stimulation of target cells
US10036758B2 (en) 2005-07-22 2018-07-31 The Board Of Trustees Of The Leland Stanford Junior University Delivery of a light-activated cation channel into the brain of a subject
US20090176725A1 (en) * 2005-08-17 2009-07-09 Sirna Therapeutics Inc. Chemically modified short interfering nucleic acid molecules that mediate rna interference
WO2007047692A3 (fr) * 2005-10-19 2007-08-02 Medtronic Inc Dispositifs, systemes et procedes destines a ameliorer la memoire et/ou la fonction cognitive par administration d'arnsi au cerveau
WO2007092563A3 (fr) * 2006-02-08 2007-11-22 Genzyme Corp Therapie genique destinee a la maladie de niemann-pick de type a
EP3456331A1 (fr) 2006-02-08 2019-03-20 Genzyme Corporation Thérapie génique destinée à la maladie de niemann-pick de type a
US8367615B2 (en) 2006-03-30 2013-02-05 Research Foundation Of City University Of New York Stimulation of neuron regeneration by secretory leukocyte protease inhibitor
US20100256065A1 (en) * 2006-03-30 2010-10-07 Research Foundation Of City University Of New York Stimulation of neuron regeneration by secretory leukocyte protease inhibitor
US9724387B2 (en) 2006-04-25 2017-08-08 The Regents Of The University Of California Administration of growth factors for the treatment of CNS disorders
US20070254842A1 (en) * 2006-04-25 2007-11-01 The Regents Of The University Of California Administration of growth factors for the treatment of cns disorders
US8409548B2 (en) 2006-04-25 2013-04-02 The Regents Of The University Of California Administration of growth factors for the treatment of CNS disorders
US7922999B2 (en) 2006-04-25 2011-04-12 The Regents Of The University Of California Administration of growth factors for the treatment of CNS disorders
US9050299B2 (en) 2006-04-25 2015-06-09 The Regents Of The University Of California Administration of growth factors for the treatment of CNS disorders
US20070259031A1 (en) * 2006-04-26 2007-11-08 The Regents Of The University Of California Compositions and methods for convection enhanced delivery of high molecular weight neurotherapeutics
US20100098639A1 (en) * 2006-04-26 2010-04-22 The Regents Of The University Of California Compositions and Methods for Convection Enhanced Delivery of High Molecular Weight Neurotherapeutics
US20080280843A1 (en) * 2006-05-24 2008-11-13 Van Bilsen Paul Methods and kits for linking polymorphic sequences to expanded repeat mutations
US9273356B2 (en) 2006-05-24 2016-03-01 Medtronic, Inc. Methods and kits for linking polymorphic sequences to expanded repeat mutations
EP2489733A2 (fr) 2006-06-07 2012-08-22 Genzyme Corporation Thérapie génique pour la sclérose latérale amyotrophique et autres troubles de la moelle épinière
WO2007146046A2 (fr) 2006-06-07 2007-12-21 Genzyme Corporation Thérapie génique destinée à traiter la sclérose latérale amyotrophique et d'autres troubles de la moelle épinière
EP3540054A2 (fr) 2006-06-07 2019-09-18 Genzyme Corporation Thérapie génique pour la sclérose latérale amyotrophique et autres troubles de la moelle épinière
US20080039415A1 (en) * 2006-08-11 2008-02-14 Gregory Robert Stewart Retrograde transport of sirna and therapeutic uses to treat neurologic disorders
EP3632472A1 (fr) 2006-10-03 2020-04-08 Genzyme Corporation Thérapie génique pour la sclérose latérale amyotrophique et autres troubles de la moelle épinière
EP3146982A1 (fr) 2006-10-03 2017-03-29 Genzyme Corporation Therapie genique visant a traiter la sclerose laterale amyotrophique et d'autres troubles de la moelle epiniere
EP2497500A1 (fr) 2006-10-03 2012-09-12 Genzyme Corporation Thérapie génique pour la sclérose latérale amyotrophique et autres troubles de la moelle épinière
US8324367B2 (en) 2006-11-03 2012-12-04 Medtronic, Inc. Compositions and methods for making therapies delivered by viral vectors reversible for safety and allele-specificity
US20080124379A1 (en) * 2006-11-03 2008-05-29 Kaemmerer William F Compositions and methods for making therapies delivered by viral vectors reversible for safety and allele-specificity
US9375440B2 (en) 2006-11-03 2016-06-28 Medtronic, Inc. Compositions and methods for making therapies delivered by viral vectors reversible for safety and allele-specificity
US20080119787A1 (en) * 2006-11-21 2008-05-22 Kaemmerer William F Microsyringe for pre-packaged delivery of pharmaceuticals
US7988668B2 (en) 2006-11-21 2011-08-02 Medtronic, Inc. Microsyringe for pre-packaged delivery of pharmaceuticals
US20080119789A1 (en) * 2006-11-21 2008-05-22 Kaemmerer William F Chronically implantable guide tube for repeated intermittent delivery of materials or fluids to targeted tissue sites
US7819842B2 (en) 2006-11-21 2010-10-26 Medtronic, Inc. Chronically implantable guide tube for repeated intermittent delivery of materials or fluids to targeted tissue sites
US10105551B2 (en) 2007-01-10 2018-10-23 The Board Of Trustees Of The Leland Stanford Junior University System for optical stimulation of target cells
US10369378B2 (en) 2007-01-10 2019-08-06 The Board Of Trustees Of The Leland Stanford Junior University System for optical stimulation of target cells
US11007374B2 (en) 2007-01-10 2021-05-18 The Board Of Trustees Of The Leland Stanford Junior University System for optical stimulation of target cells
US20080171906A1 (en) * 2007-01-16 2008-07-17 Everaerts Frank J L Tissue performance via hydrolysis and cross-linking
US9693692B2 (en) 2007-02-14 2017-07-04 The Board Of Trustees Of The Leland Stanford Junior University System, method and applications involving identification of biological circuits such as neurological characteristics
US9855442B2 (en) 2007-03-01 2018-01-02 The Board Of Trustees Of The Leland Stanford Junior University Method for optically controlling a neuron with a mammalian codon optimized nucleotide sequence that encodes a variant opsin polypeptide derived from natromonas pharaonis (NpHR)
US9757587B2 (en) 2007-03-01 2017-09-12 The Board Of Trustees Of The Leland Stanford Junior University Optogenetic method for generating an inhibitory current in a mammalian neuron
US10589123B2 (en) 2007-03-01 2020-03-17 The Board Of Trustees Of The Leland Stanford Junior University Systems, methods and compositions for optical stimulation of target cells
US7968524B2 (en) 2007-05-15 2011-06-28 Helicon Therapeutics, Inc. Methods of enhancing long term memory formation by inhibition of Gpr12
US20090022667A1 (en) * 2007-05-15 2009-01-22 Marco Peters METHODS OF TREATING COGNITIVE DISORDERS BY INHIBITION OF Gpr12
EP3000320A1 (fr) 2007-05-16 2016-03-30 The Brigham and Women's Hospital, Inc. Traitement de synucléinopathies
WO2008154198A1 (fr) 2007-06-06 2008-12-18 Genzyme Corporation Thérapie génique pour les maladies de stockage lysosomal
US11369693B2 (en) 2007-06-06 2022-06-28 Genzyme Corporation Gene therapy for lysosomal storage diseases
EP3252161A1 (fr) 2007-06-06 2017-12-06 Genzyme Corporation Thérapie génique pour les maladies de stockage lysosomal
US20100240441A1 (en) * 2007-09-14 2010-09-23 Konami Digital Entertainment Co., Ltd Game system, and game apparatus and challenge notifying apparatus constituting the game system
US10035027B2 (en) 2007-10-31 2018-07-31 The Board Of Trustees Of The Leland Stanford Junior University Device and method for ultrasonic neuromodulation via stereotactic frame based technique
US10426970B2 (en) 2007-10-31 2019-10-01 The Board Of Trustees Of The Leland Stanford Junior University Implantable optical stimulators
US10434327B2 (en) 2007-10-31 2019-10-08 The Board Of Trustees Of The Leland Stanford Junior University Implantable optical stimulators
WO2009123764A2 (fr) 2008-04-04 2009-10-08 Calando Pharmaceuticals, Inc. Compositions et utilisation d'inhibiteurs d'epas1
US9878176B2 (en) 2008-04-23 2018-01-30 The Board Of Trustees Of The Leland Stanford Junior University System utilizing Volvox carteri light-activated ion channel protein (VChR1) for optical stimulation of target cells
US9394347B2 (en) 2008-04-23 2016-07-19 The Board Of Trustees Of The Leland Stanford Junior University Methods for treating parkinson's disease by optically stimulating target cells
US10350430B2 (en) 2008-04-23 2019-07-16 The Board Of Trustees Of The Leland Stanford Junior University System comprising a nucleotide sequence encoding a volvox carteri light-activated ion channel protein (VCHR1)
US9453215B2 (en) 2008-05-29 2016-09-27 The Board Of Trustees Of The Leland Stanford Junior University Cell line, system and method for optical control of secondary messengers
US10711242B2 (en) 2008-06-17 2020-07-14 The Board Of Trustees Of The Leland Stanford Junior University Apparatus and methods for controlling cellular development
US10583309B2 (en) 2008-07-08 2020-03-10 The Board Of Trustees Of The Leland Stanford Junior University Materials and approaches for optical stimulation of the peripheral nervous system
US10064912B2 (en) 2008-11-14 2018-09-04 The Board Of Trustees Of The Leland Stanford Junior University Optically-based stimulation of target cells and modifications thereto
US10071132B2 (en) 2008-11-14 2018-09-11 The Board Of Trustees Of The Leland Stanford Junior University Optically-based stimulation of target cells and modifications thereto
US9458208B2 (en) 2008-11-14 2016-10-04 The Board Of Trustees Of The Leland Stanford Junior University Optically-based stimulation of target cells and modifications thereto
WO2010071454A1 (fr) * 2008-12-17 2010-06-24 Auckland Uniservices Limited Vecteurs viraux adéno-associés et leurs utilisations
WO2010083842A2 (fr) 2009-01-23 2010-07-29 Nsgene A/S Expression de neuropeptides dans des cellules mammaliennes
US11834474B2 (en) 2009-05-28 2023-12-05 University Of Massachusetts AAV's and uses thereof
US20180362592A1 (en) * 2009-05-28 2018-12-20 University Of Massachusetts Novel aav's and uses thereof
US10689420B2 (en) * 2009-05-28 2020-06-23 University Of Massachusetts AAV's and uses thereof
EP3434773A2 (fr) 2009-12-09 2019-01-30 Nitto Denko Corporation Modulation de l'expression de hsp47
US8710209B2 (en) 2009-12-09 2014-04-29 Nitto Denko Corporation Modulation of HSP47 expression
US20110178157A1 (en) * 2009-12-09 2011-07-21 Nitto Denko Technical Corporation Modulation of hsp47 expression
US10093923B2 (en) 2009-12-09 2018-10-09 Nitto Denko Corporation Modulation of HSP47 expression
EP3012324A2 (fr) 2009-12-09 2016-04-27 Nitto Denko Corporation Modulation de l'expression hsp47
US9206424B2 (en) 2009-12-09 2015-12-08 Nitto Denko Corporation Modulation of HSP47 expression
US9604073B2 (en) 2010-03-17 2017-03-28 The Board Of Trustees Of The Leland Stanford Junior University Light-sensitive ion-passing molecules
US10731178B2 (en) 2010-04-23 2020-08-04 University Of Massachusetts CNS targeting AAV vectors and methods of use thereof
WO2011163436A1 (fr) 2010-06-24 2011-12-29 Quark Pharmaceuticals, Inc. Composés à base d'arn double brin pour le gène rhoa et leur utilisation
US9260471B2 (en) 2010-10-29 2016-02-16 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acids (siNA)
US11193126B2 (en) 2010-10-29 2021-12-07 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acids (siNA)
US9970005B2 (en) 2010-10-29 2018-05-15 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acids (siNA)
US11932854B2 (en) 2010-10-29 2024-03-19 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acids (siNA)
US10196431B2 (en) 2010-11-05 2019-02-05 The Board Of Trustees Of The Leland Stanford Junior University Light-activated chimeric opsins and methods of using the same
US10568307B2 (en) 2010-11-05 2020-02-25 The Board Of Trustees Of The Leland Stanford Junior University Stabilized step function opsin proteins and methods of using the same
US9992981B2 (en) 2010-11-05 2018-06-12 The Board Of Trustees Of The Leland Stanford Junior University Optogenetic control of reward-related behaviors
US9968652B2 (en) 2010-11-05 2018-05-15 The Board Of Trustees Of The Leland Stanford Junior University Optically-controlled CNS dysfunction
US10252076B2 (en) 2010-11-05 2019-04-09 The Board Of Trustees Of The Leland Stanford Junior University Upconversion of light for use in optogenetic methods
US10086012B2 (en) 2010-11-05 2018-10-02 The Board Of Trustees Of The Leland Stanford Junior University Control and characterization of memory function
US9850290B2 (en) 2010-11-05 2017-12-26 The Board Of Trustees Of The Leland Stanford Junior University Light-activated chimeric opsins and methods of using the same
US9522288B2 (en) 2010-11-05 2016-12-20 The Board Of Trustees Of The Leland Stanford Junior University Upconversion of light for use in optogenetic methods
US9615789B2 (en) 2010-11-22 2017-04-11 The Board Of Trustees Of The Leland Stanford Junior University Optogenetic magnetic resonance imaging
US10371776B2 (en) 2010-11-22 2019-08-06 The Board Of Trustees Of The Leland Stanford Junior University Optogenetic magnetic resonance imaging
US10018695B2 (en) 2010-11-22 2018-07-10 The Board Of Trustees Of The Leland Stanford Junior University Optogenetic magnetic resonance imaging
US10914803B2 (en) 2010-11-22 2021-02-09 The Board Of Trustees Of The Leland Stanford Junior University Optogenetic magnetic resonance imaging
US10195145B2 (en) 2011-06-08 2019-02-05 Nitto Denko Corporation Method for treating fibrosis using siRNA and a retinoid-lipid drug carrier
EP2998289A1 (fr) 2011-06-08 2016-03-23 Nitto Denko Corporation Composés pour cibler l'administration de médicaments et renforcer l'activité arnsi
US10196637B2 (en) 2011-06-08 2019-02-05 Nitto Denko Corporation Retinoid-lipid drug carrier
WO2012170952A2 (fr) 2011-06-08 2012-12-13 Nitto Denko Corporation Composés pour l'administration de médicament ciblée et l'augmentation de l'activité arnsi
EP3075855A1 (fr) 2011-06-08 2016-10-05 Nitto Denko Corporation Liposomes-rétinoïde pour améliorer la modulation de l'expression hsp47
US9456984B2 (en) 2011-06-08 2016-10-04 Nitto Denko Corporation Method for treating fibrosis using siRNA and a retinoid-lipid drug carrier
US10532975B2 (en) 2011-06-08 2020-01-14 Nitto Denko Corporation Cationic lipids for therapeutic agent delivery formulations
US8664376B2 (en) 2011-06-08 2014-03-04 Nitto Denko Corporation Retinoid-liposomes for enhancing modulation of HSP47 expression
US11084779B2 (en) 2011-06-08 2021-08-10 Nitto Denko Corporation Cationic lipids for therapeutic agent delivery formulations
US9242001B2 (en) 2011-06-08 2016-01-26 Nitto Denko Corporation Cationic lipids for therapeutic agent delivery formulations
US9963424B2 (en) 2011-06-08 2018-05-08 Nitto Denko Corporation Cationic lipids for therapeutic agent delivery formulations
WO2012170957A2 (fr) 2011-06-08 2012-12-13 Nitto Denko Corporation Liposomes-rétinoïdes permettant d'améliorer la modulation de l'expression de hsp47
US9011903B2 (en) 2011-06-08 2015-04-21 Nitto Denko Corporation Cationic lipids for therapeutic agent delivery formulations
US8741867B2 (en) 2011-06-08 2014-06-03 Nitto Denko Corporation Retinoid-liposomes for treating fibrosis
US9840541B2 (en) 2011-12-16 2017-12-12 The Board Of Trustees Of The Leland Stanford Junior University Opsin polypeptides and methods of use thereof
US9505817B2 (en) 2011-12-16 2016-11-29 The Board Of Trustees Of The Leland Stanford Junior University Opsin polypeptides and methods of use thereof
US10538560B2 (en) 2011-12-16 2020-01-21 The Board Of Trustees Of The Leland Stanford Junior University Opsin polypeptides and methods of use thereof
US9969783B2 (en) 2011-12-16 2018-05-15 The Board Of Trustees Of The Leland Stanford Junior University Opsin polypeptides and methods of use thereof
US10087223B2 (en) 2011-12-16 2018-10-02 The Board Of Trustees Of The Leland Stanford Junior University Opsin polypeptides and methods of use thereof
US11103723B2 (en) 2012-02-21 2021-08-31 The Board Of Trustees Of The Leland Stanford Junior University Methods for treating neurogenic disorders of the pelvic floor
US9636380B2 (en) 2013-03-15 2017-05-02 The Board Of Trustees Of The Leland Stanford Junior University Optogenetic control of inputs to the ventral tegmental area
US10974064B2 (en) 2013-03-15 2021-04-13 The Board Of Trustees Of The Leland Stanford Junior University Optogenetic control of behavioral state
US10220092B2 (en) 2013-04-29 2019-03-05 The Board Of Trustees Of The Leland Stanford Junior University Devices, systems and methods for optogenetic modulation of action potentials in target cells
US10307609B2 (en) 2013-08-14 2019-06-04 The Board Of Trustees Of The Leland Stanford Junior University Compositions and methods for controlling pain
US11021696B2 (en) 2013-11-13 2021-06-01 Children's Medical Center Corporation Nuclease-mediated regulation of gene expression
EP3492593A1 (fr) 2013-11-13 2019-06-05 Children's Medical Center Corporation Régulation de l'expression génique médiée par la nucléase
US10577627B2 (en) 2014-06-09 2020-03-03 Voyager Therapeutics, Inc. Chimeric capsids
US11542525B2 (en) 2014-10-21 2023-01-03 University Of Massachusetts Recombinant AAV variants and uses thereof
US11975056B2 (en) 2014-11-05 2024-05-07 Voyager Therapeutics, Inc. AADC polynucleotides for the treatment of Parkinson's disease
US11027000B2 (en) 2014-11-05 2021-06-08 Voyager Therapeutics, Inc. AADC polynucleotides for the treatment of Parkinson's disease
US10335466B2 (en) 2014-11-05 2019-07-02 Voyager Therapeutics, Inc. AADC polynucleotides for the treatment of parkinson's disease
US11198873B2 (en) 2014-11-14 2021-12-14 Voyager Therapeutics, Inc. Modulatory polynucleotides
US10597660B2 (en) 2014-11-14 2020-03-24 Voyager Therapeutics, Inc. Compositions and methods of treating amyotrophic lateral sclerosis (ALS)
US12123002B2 (en) 2014-11-14 2024-10-22 Voyager Therapeutics, Inc. Compositions and methods of treating amyotrophic lateral sclerosis (ALS)
US10920227B2 (en) 2014-11-14 2021-02-16 Voyager Therapeutics, Inc. Compositions and methods of treating amyotrophic lateral sclerosis (ALS)
US10570395B2 (en) 2014-11-14 2020-02-25 Voyager Therapeutics, Inc. Modulatory polynucleotides
US12071625B2 (en) 2014-11-14 2024-08-27 Voyager Therapeutics, Inc. Modulatory polynucleotides
US11542506B2 (en) 2014-11-14 2023-01-03 Voyager Therapeutics, Inc. Compositions and methods of treating amyotrophic lateral sclerosis (ALS)
US11697825B2 (en) 2014-12-12 2023-07-11 Voyager Therapeutics, Inc. Compositions and methods for the production of scAAV
WO2016164642A1 (fr) 2015-04-08 2016-10-13 The United States Of America, As Represented By The Secretary Of Health And Human Services Thérapie génique virale à utiliser en tant que traitement pour une maladie ou un trouble associé au stockage du cholestérol
US10967073B2 (en) 2015-05-07 2021-04-06 The Mclean Hospital Corporation Glucocerebrosidase gene therapy for Parkinson's disease
WO2016179497A1 (fr) 2015-05-07 2016-11-10 Shire Human Genetic Therapies, Inc. Thérapie génique par glucocérébrosidase pour la maladie de parkinson
US10016514B2 (en) 2015-05-15 2018-07-10 New Hope Research Foundation Polynucleotides, vectors and methods for insertion and expression of transgenes
US10568516B2 (en) 2015-06-22 2020-02-25 The Board Of Trustees Of The Leland Stanford Junior University Methods and devices for imaging and/or optogenetic control of light-responsive neurons
WO2017075335A1 (fr) 2015-10-28 2017-05-04 Voyager Therapeutics, Inc. Expression régulable au moyen d'un virus adéno-associé (vaa)
US11326182B2 (en) 2016-04-29 2022-05-10 Voyager Therapeutics, Inc. Compositions for the treatment of disease
US11299751B2 (en) 2016-04-29 2022-04-12 Voyager Therapeutics, Inc. Compositions for the treatment of disease
US11193129B2 (en) 2016-05-18 2021-12-07 Voyager Therapeutics, Inc. Modulatory polynucleotides
US11951121B2 (en) 2016-05-18 2024-04-09 Voyager Therapeutics, Inc. Compositions and methods for treating Huntington's disease
US10584337B2 (en) 2016-05-18 2020-03-10 Voyager Therapeutics, Inc. Modulatory polynucleotides
US12084659B2 (en) 2016-05-18 2024-09-10 Voyager Therapeutics, Inc. Modulatory polynucleotides
US11298041B2 (en) 2016-08-30 2022-04-12 The Regents Of The University Of California Methods for biomedical targeting and delivery and devices and systems for practicing the same
US11578340B2 (en) 2016-10-13 2023-02-14 University Of Massachusetts AAV capsid designs
US11294165B2 (en) 2017-03-30 2022-04-05 The Board Of Trustees Of The Leland Stanford Junior University Modular, electro-optical device for increasing the imaging field of view using time-sequential capture
US10287608B2 (en) 2017-04-03 2019-05-14 Encoded Therapeutics, Inc. Tissue selective transgene expression
US10519465B2 (en) 2017-04-03 2019-12-31 Encoded Therapeutics, Inc. Tissue selective transgene expression
US10287607B2 (en) 2017-04-03 2019-05-14 Encoded Therapeutics, Inc. Tissue selective transgene expression
US11603542B2 (en) 2017-05-05 2023-03-14 Voyager Therapeutics, Inc. Compositions and methods of treating amyotrophic lateral sclerosis (ALS)
US11752181B2 (en) 2017-05-05 2023-09-12 Voyager Therapeutics, Inc. Compositions and methods of treating Huntington's disease
US11759506B2 (en) 2017-06-15 2023-09-19 Voyager Therapeutics, Inc. AADC polynucleotides for the treatment of Parkinson's disease
WO2018237066A1 (fr) 2017-06-20 2018-12-27 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Gènes npc1 humains optimisés par des codons pour le traitement d'une maladie de niemann-pick de type c1 et d'états associés
US11497576B2 (en) 2017-07-17 2022-11-15 Voyager Therapeutics, Inc. Trajectory array guide system
WO2019028306A2 (fr) 2017-08-03 2019-02-07 Voyager Therapeutics, Inc. Compositions et procédés permettant l'administration de virus adéno-associés
US11512327B2 (en) 2017-08-03 2022-11-29 Voyager Therapeutics, Inc. Compositions and methods for delivery of AAV
EP3808849A1 (fr) 2017-08-03 2021-04-21 Voyager Therapeutics, Inc. Compositions et procédés pour l'administration d'aav
US12116589B2 (en) 2017-10-16 2024-10-15 Voyager Therapeutics, Inc. Treatment of amyotrophic lateral sclerosis (ALS)
EP4454654A2 (fr) 2017-10-16 2024-10-30 Voyager Therapeutics, Inc. Traitement de la sclérose latérale amyotrophique (sla)
US11931375B2 (en) 2017-10-16 2024-03-19 Voyager Therapeutics, Inc. Treatment of amyotrophic lateral sclerosis (ALS)
WO2019079242A1 (fr) 2017-10-16 2019-04-25 Voyager Therapeutics, Inc. Traitement de la sclérose latérale amyotrophique (sla)
WO2019079240A1 (fr) 2017-10-16 2019-04-25 Voyager Therapeutics, Inc. Traitement de la sclérose latérale amyotrophique (sla)
EP4124658A2 (fr) 2017-10-16 2023-02-01 Voyager Therapeutics, Inc. Traitement de la sclérose latérale amyotrophique (sla)
US11434502B2 (en) 2017-10-16 2022-09-06 Voyager Therapeutics, Inc. Treatment of amyotrophic lateral sclerosis (ALS)
US12083188B2 (en) 2017-12-01 2024-09-10 Encoded Therapeutics, Inc. Engineered DNA binding proteins
US11951183B2 (en) 2018-02-01 2024-04-09 Homology Medicines, Inc. Adeno-associated virus compositions for PAH gene transfer and methods of use thereof
US10610606B2 (en) 2018-02-01 2020-04-07 Homology Medicines, Inc. Adeno-associated virus compositions for PAH gene transfer and methods of use thereof
US12064486B2 (en) 2018-02-01 2024-08-20 Homology Medicines, Inc. Adeno-associated virus compositions for PAH gene transfer and methods of use thereof
US11891619B2 (en) 2018-02-19 2024-02-06 City Of Hope Adeno-associated virus compositions for restoring F8 gene function and methods of use thereof
US11306329B2 (en) 2018-02-19 2022-04-19 City Of Hope Adeno-associated virus compositions for restoring F8 gene function and methods of use thereof
WO2019173434A1 (fr) 2018-03-06 2019-09-12 Voyager Therapeutics, Inc. Génomes aav partiels auto-complémentaires fabriqués par des cellules d'insectes
US12060390B2 (en) 2018-04-03 2024-08-13 Ginkgo Bioworks, Inc. Antibody-evading virus vectors
US12091435B2 (en) 2018-04-03 2024-09-17 Ginkgo Bioworks, Inc. Antibody-evading virus vectors
US11976096B2 (en) 2018-04-03 2024-05-07 Ginkgo Bioworks, Inc. Antibody-evading virus vectors
US12116384B2 (en) 2018-04-03 2024-10-15 Ginkgo Bioworks, Inc. Virus vectors for targeting ophthalmic tissues
WO2019222329A1 (fr) 2018-05-15 2019-11-21 Voyager Therapeutics, Inc. Compositions et procédés pour l'administration de vaa
WO2019222441A1 (fr) 2018-05-16 2019-11-21 Voyager Therapeutics, Inc. Sérotypes de vaa pour l'administration de charge utile spécifique au cerveau
WO2019222444A2 (fr) 2018-05-16 2019-11-21 Voyager Therapeutics, Inc. Évolution dirigée
WO2019241486A1 (fr) 2018-06-13 2019-12-19 Voyager Therapeutics, Inc. Régions 5' non traduites (5'utr) modifiées pour la production d'aav
WO2020010042A1 (fr) 2018-07-02 2020-01-09 Voyager Therapeutics, Inc. Traitement de la sclérose latérale amyotrophique et de troubles associés à la moelle épinière
WO2020010035A1 (fr) 2018-07-02 2020-01-09 Voyager Therapeutics, Inc. Système de canule
WO2020023612A1 (fr) 2018-07-24 2020-01-30 Voyager Therapeutics, Inc. Systèmes et méthodes de production de formulations de thérapie génique
WO2020069461A1 (fr) 2018-09-28 2020-04-02 Voyager Therapeutics, Inc. Constructions d'expression de frataxine comprenant des promoteurs modifiés et leurs méthodes d'utilisation
WO2020072849A1 (fr) 2018-10-04 2020-04-09 Voyager Therapeutics, Inc. Procédés de mesure du titre et de la puissance de particules de vecteur viral
WO2020072844A1 (fr) 2018-10-05 2020-04-09 Voyager Therapeutics, Inc. Constructions d'acides nucléiques modifiés codant pour des protéines de production d'aav
WO2020077165A1 (fr) 2018-10-12 2020-04-16 Voyager Therapeutics, Inc. Compositions et procédés pour l'administration d'aav
WO2020081490A1 (fr) 2018-10-15 2020-04-23 Voyager Therapeutics, Inc. Vecteurs d'expression pour la production à grande échelle de raav dans le système baculovirus/sf9
WO2020150556A1 (fr) 2019-01-18 2020-07-23 Voyager Therapeutics, Inc. Procédés et systèmes de fabrication de particules aav
US11981914B2 (en) 2019-03-21 2024-05-14 Ginkgo Bioworks, Inc. Recombinant adeno-associated virus vectors
WO2020223274A1 (fr) 2019-04-29 2020-11-05 Voyager Therapeutics, Inc. Système et procédé pour la production de cellules d'insectes infectées par baculovirus (ceib) dans les bioréacteurs
WO2021030125A1 (fr) 2019-08-09 2021-02-18 Voyager Therapeutics, Inc. Milieu de culture cellulaire destiné à être utilisé dans la production de produits de thérapie génique dans des bioréacteurs
WO2021041485A1 (fr) 2019-08-26 2021-03-04 Voyager Therapeutics, Inc. Expression contrôlée de protéines virales
US11905523B2 (en) 2019-10-17 2024-02-20 Ginkgo Bioworks, Inc. Adeno-associated viral vectors for treatment of Niemann-Pick Disease type-C
US11952585B2 (en) 2020-01-13 2024-04-09 Homology Medicines, Inc. Methods of treating phenylketonuria
US12076420B2 (en) 2020-05-27 2024-09-03 Homology Medicines, Inc. Adeno-associated virus compositions for restoring PAH gene function and methods of use thereof
WO2021247995A2 (fr) 2020-06-04 2021-12-09 Voyager Therapeutics, Inc. Compositions et méthodes de traitement de la douleur neuropathique
WO2022018171A1 (fr) 2020-07-23 2022-01-27 Ucl Business Ltd Vecteur de thérapie génique pour eef1a2 et ses utilisations
WO2022017630A1 (fr) 2020-07-23 2022-01-27 Ucl Business Ltd Vecteur de thérapie génique pour eef1a2 et ses utilisations
WO2022026410A2 (fr) 2020-07-27 2022-02-03 Voyager Therapeutics, Inc Compositions et méthodes pour le traitement de la maladie de niemann-pick de type c1
WO2022026409A1 (fr) 2020-07-27 2022-02-03 Voyager Therapeutics, Inc. Compositions et procédés pour le traitement des troubles neurologiques liés au déficit en glucosylcéramidase bêta
WO2022032153A1 (fr) 2020-08-06 2022-02-10 Voyager Therapeutics, Inc. Milieu de culture cellulaire destiné à être utilisé dans la production de produits de thérapie génique dans des bioréacteurs
US12104163B2 (en) 2020-08-19 2024-10-01 Sarepta Therapeutics, Inc. Adeno-associated virus vectors for treatment of Rett syndrome
WO2022187548A1 (fr) 2021-03-03 2022-09-09 Voyager Therapeutics, Inc. Expression régulée de protéines virales
WO2022187473A2 (fr) 2021-03-03 2022-09-09 Voyager Therapeutics, Inc. Expression contrôlée de protéines virales
WO2023091949A2 (fr) 2021-11-17 2023-05-25 Voyager Therapeutics, Inc. Compositions et méthodes de traitement de troubles neurologiques liés à un déficit en bêta glucosylcéramidase
WO2023092004A1 (fr) 2021-11-17 2023-05-25 Voyager Therapeutics, Inc. Compositions et méthodes pour le traitement de troubles liés à tau
WO2024054983A1 (fr) 2022-09-08 2024-03-14 Voyager Therapeutics, Inc. Expression controlée de protéines virales
US12146150B2 (en) 2022-09-13 2024-11-19 Voyager Therapeutics, Inc. Rescue of central and peripheral neurological phenotype of friedreich's ataxia by intravenous delivery
WO2024140306A1 (fr) * 2022-12-26 2024-07-04 科辉智药(深圳)新药研究中心有限公司 Structure de séquence génique pour le traitement de maladies du système nerveux central et son utilisation
WO2024145474A2 (fr) 2022-12-29 2024-07-04 Voyager Therapeutics, Inc. Compositions et procédés de régulation de mapt
WO2024163012A1 (fr) 2023-02-02 2024-08-08 Voyager Therapeutics, Inc. Compositions et méthodes de traitement de troubles neurologiques liés à un déficit en bêta glucosylcéramidase
WO2024163737A1 (fr) 2023-02-02 2024-08-08 Voyager Therapeutics, Inc. Compositions et méthodes pour le traitement de troubles neurologiques liés à une déficience en glucosylcéramidase bêta 1
WO2024161032A1 (fr) 2023-02-03 2024-08-08 Janssen Pharmaceutica Nv Vecteurs de thérapie génique pour le traitement de la maladie de parkinson
WO2024226761A2 (fr) 2023-04-26 2024-10-31 Voyager Therapeutics, Inc. Compositions et méthodes de traitement de la sclérose latérale amyotrophique

Also Published As

Publication number Publication date
US6503888B1 (en) 2003-01-07
CA2187626A1 (fr) 1995-10-26
CA2187626C (fr) 2009-11-03
EP0755454A1 (fr) 1997-01-29
JPH10501686A (ja) 1998-02-17
JP4843663B2 (ja) 2011-12-21
WO1995028493A1 (fr) 1995-10-26
DE69535703T2 (de) 2009-02-19
JP2009060919A (ja) 2009-03-26
ATE386131T1 (de) 2008-03-15
DE69535703D1 (de) 2008-03-27
JP2006051038A (ja) 2006-02-23
EP0755454B1 (fr) 2008-02-13

Similar Documents

Publication Publication Date Title
US6180613B1 (en) AAV-mediated delivery of DNA to cells of the nervous system
Kaplitt et al. Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain
US20240350673A1 (en) Methods and compositions for inhibiting oxidative stress
US6780409B2 (en) Glutamic acid decarboxylase (GAD) based delivery system
US7811814B2 (en) Tetracycline-regulated adeno-associated viral (AAV) vectors for gene delivery to the nervous system
Hsich et al. Critical issues in gene therapy for neurologic disease
US6936243B2 (en) Adeno-associated viral vector-mediated delivery of DNA to cells of the liver
US7955595B2 (en) Glutamic acid decarboxylase (GAD) based delivery system
AU2001268080A1 (en) Glutamic acid decarboxylase (gad) based delivery systems
Alisky et al. Gene therapy for amyotrophic lateral sclerosis and other motor neuron diseases
MX2007006807A (es) Expresion regulada de transgenes en el sistema nervioso central de mamiferos.
WO1997039629A1 (fr) Vecteurs viraux incluant des polynucleotides codant des facteurs neurotrophiques ainsi que leur utilisation
JP2005507927A (ja) パーキンソン病を処置するための方法および組成物
Kaplitt et al. Transfer and expression of potentially therapeutic genes into the mammalian central nervous system in vivo using adeno-associated viral vectors
Muramatsu et al. Adeno-associated viral vectors for Parkinson's disease
AU2004101085A4 (en) Glutamic acid decarboxylase (GAD)based delivery systems
Isenmann Viral gene delivery

Legal Events

Date Code Title Description
AS Assignment

Owner name: ROCKEFELLER UNIVERSITY, THE, NEW YORK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:KAPLITT, MICHAEL G.;REEL/FRAME:007675/0862

Effective date: 19950828

Owner name: YALE UNIVERSITY, CONNECTICUT

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:DURING, MATTHEW J.;REEL/FRAME:007675/0848

Effective date: 19950911

STCF Information on status: patent grant

Free format text: PATENTED CASE

FPAY Fee payment

Year of fee payment: 4

FPAY Fee payment

Year of fee payment: 8

FPAY Fee payment

Year of fee payment: 12